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Sample records for regulating longevity stress

  1. Two Conserved Histone Demethylases Regulate Mitochondrial Stress-Induced Longevity.

    PubMed

    Merkwirth, Carsten; Jovaisaite, Virginija; Durieux, Jenni; Matilainen, Olli; Jordan, Sabine D; Quiros, Pedro M; Steffen, Kristan K; Williams, Evan G; Mouchiroud, Laurent; Tronnes, Sarah U; Murillo, Virginia; Wolff, Suzanne C; Shaw, Reuben J; Auwerx, Johan; Dillin, Andrew

    2016-05-19

    Across eukaryotic species, mild mitochondrial stress can have beneficial effects on the lifespan of organisms. Mitochondrial dysfunction activates an unfolded protein response (UPR(mt)), a stress signaling mechanism designed to ensure mitochondrial homeostasis. Perturbation of mitochondria during larval development in C. elegans not only delays aging but also maintains UPR(mt) signaling, suggesting an epigenetic mechanism that modulates both longevity and mitochondrial proteostasis throughout life. We identify the conserved histone lysine demethylases jmjd-1.2/PHF8 and jmjd-3.1/JMJD3 as positive regulators of lifespan in response to mitochondrial dysfunction across species. Reduction of function of the demethylases potently suppresses longevity and UPR(mt) induction, while gain of function is sufficient to extend lifespan in a UPR(mt)-dependent manner. A systems genetics approach in the BXD mouse reference population further indicates conserved roles of the mammalian orthologs in longevity and UPR(mt) signaling. These findings illustrate an evolutionary conserved epigenetic mechanism that determines the rate of aging downstream of mitochondrial perturbations. PMID:27133168

  2. Regulation of longevity and stress resistance: a molecular strategy conserved from yeast to humans?

    PubMed

    Longo, V D; Fabrizio, P

    2002-06-01

    Recent studies implicate similar proteins in the regulation of longevity in organisms ranging from yeast to mice. Studies in yeast and worms suggest that inactivation of glucose or insulin/insulin-like growth factor-l (IGF-1) signaling pathways extends longevity by causing a shift from a reproductive phase to a non-reproductive maintenance phase involving the expression of many genes. These stress resistance pathways appear to have evolved to induce maintenance systems and promote longevity during periods of starvation. In yeast, mutations that decrease the activity of glucose signaling pathways extend longevity by activating stress resistance transcription factors that regulate the expression of genes involved in antioxidant and heat protection, glycogen storage, protein degradation, DNA repair, and metabolism. A remarkably similar set of proteins regulated by growth factors that control glucose metabolism is implicated in life span extension in worms, and possibly in flies and mice. Studies in worms and flies point to secondary hormones as mediators of the effect of insulin/ IGF-1 signaling on longevity, whereas studies in yeast and mammalian cells indicate that glucose or insulin/ IGF-1 may decrease longevity by directly down-regulating stress resistance genes. In yeast, longevity mutations postpone superoxide toxicity and mitochondrial damage. However, the small life span extension caused by the overexpression of superoxide dismutases and catalase in yeast and flies indicates that increased antioxidant protection alone cannot be responsible for the major life span extension caused by signal transduction mutations. Although we are only beginning to understand the molecular mechanisms that mediate life span extension, the similarities between longevity regulatory pathways in organisms ranging from yeast to mice suggest that insulin/ IGF-1 signaling pathways may also regulate cell damage and longevity in humans. PMID:12169020

  3. Condition-adapted stress and longevity gene regulation by Caenorhabditis elegans SKN-1/Nrf

    PubMed Central

    Oliveira, Riva P.; Porter Abate, Jess; Dilks, Kieran; Landis, Jessica; Ashraf, Jasmine; Murphy, Coleen T.; Blackwell, T. Keith

    2009-01-01

    Summary Studies in model organisms have identified regulatory processes that profoundly influence aging, many of which modulate resistance against environmental or metabolic stresses. In C. elegans the transcription regulator SKN-1 is important for oxidative stress resistance and acts in multiple longevity pathways. SKN-1 is the ortholog of mammalian Nrf proteins, which induce Phase 2 detoxification genes in response to stress. Phase 2 enzymes defend against oxygen radicals and conjugate electrophiles that are produced by Phase 1 detoxification enzymes, which metabolize lipophilic compounds. Here we have used expression profiling to identify genes and processes that are regulated by SKN-1 under normal and stress-response conditions. Under non-stressed conditions SKN-1 upregulates numerous genes involved in detoxification, cellular repair, and other functions, and downregulates a set of genes that reduce stress resistance and lifespan. Many of these genes appear to be direct SKN-1 targets, based upon presence of predicted SKN-binding sites in their promoters. The metalloid sodium arsenite induces skn-1-dependent activation of certain detoxification gene groups, including some that were not SKN-1-upregulated under normal conditions. An organic peroxide also triggers induction of a discrete Phase 2 gene set, but additionally stimulates a broad SKN-1-independent response. We conclude that under normal conditions SKN-1 has a wide range of functions in detoxification and other processes, including modulating mechanisms that reduce lifespan. In response to stress, SKN-1 and other regulators tailor transcription programs to meet the challenge at hand. Our findings reveal striking complexity in SKN-1 functions and the regulation of systemic detoxification defenses. PMID:19575768

  4. Regulation of longevity by the reproductive system.

    PubMed

    Antebi, Adam

    2013-07-01

    Pioneering work in model organisms reveals that the reproductive system is involved not only in propagation of the species but also regulates organismal metabolism and longevity. In C. elegans, prevention of germline stem cell proliferation results in a 60% extension of lifespan, termed gonadal longevity. Gonadal longevity relies on the transcriptional activities of steroid nuclear receptor DAF-12, the FOXO transcription factor homolog DAF-16, the FOXA transcription factor homolog PHA-4, and the HNF-4-like nuclear receptor NHR-80. These transcription factors work in an integrated transcriptional network to regulate fatty acid lipolysis, autophagy, stress resistance and other processes, which altogether enhance homeostasis and extend life. Because the reproductive system also regulates longevity in other species, studies in C. elegans may shed light on ancient mechanisms governing reproduction and survival. PMID:23063987

  5. Regulation of metabolism in Caenorhabditis elegans longevity.

    PubMed

    Gallo, Marco; Riddle, Donald L

    2010-01-01

    The nematode Caenorhabditis elegans is a favorite model for the study of aging. A wealth of genetic and genomic studies show that metabolic regulation is a hallmark of life-span modulation. A recent study in BMC Biology identifying metabolic signatures for longevity suggests that amino-acid pools may be important in longevity. PMID:20156326

  6. A Cytoprotective Perspective on Longevity Regulation

    PubMed Central

    Shore, David E.; Ruvkun, Gary

    2014-01-01

    There are many mechanisms of lifespan extension, including the disruption of insulin/IGF-1 signaling, metabolism, translation, or feeding. Despite the disparate functions of these pathways, inhibition of each induces responses that buffer stress and damage. Here, emphasizing data from genetic analyses in C. elegans, we explore the effectors and upstream regulatory components of numerous cytoprotective mechanisms activated as major elements of longevity programs, including detoxification, innate immunity, proteostasis, and oxidative stress response. We show that their induction underpins longevity extension across functionally diverse triggers and across species. Intertwined with the evolution of longevity, cytoprotective pathways are coupled to the surveillance of core cellular components, with important implications in normal and aberrant responses to drugs, chemicals, and pathogens. PMID:23726168

  7. A peroxiredoxin, PRDX-2, is required for insulin secretion and insulin/IIS-dependent regulation of stress resistance and longevity.

    PubMed

    Oláhová, Monika; Veal, Elizabeth A

    2015-08-01

    Peroxiredoxins (Prx) are abundant thiol peroxidases with a conserved anti-ageing role. In contrast to most animals, the nematode worm, Caenorhabditis elegans, encodes a single cytosolic 2-Cys Prx, PRDX-2, rendering it an excellent model for examining how peroxiredoxins affect animal physiology and ageing. Our previous work revealed that, although PRDX-2 protects against the toxicity of peroxides, enigmatically, prdx-2-mutant animals are hyper-resistant to other forms of oxidative stress. Here, we have investigated the basis for this increased resistance. Mammalian FOXO and Nrf2 transcription factors directly promote the expression of a range of detoxification enzymes. We show that the FOXO orthologue, DAF-16, and the Nrf2 orthologue, SKN-1, are required for the increased stress resistance of prdx-2-mutant worms. Our data suggest that PRDX-2 is required for normal levels of insulin secretion and hence the inhibition of DAF-16 and SKN-1 by insulin/IGF-1-like signalling (IIS) under nutrient-rich conditions. Intriguingly, loss of PRDX-2 increases DAF-16 and SKN-1 activities sufficiently to increase arsenite resistance without initiating other IIS-inhibited processes. Together, these data suggest that loss of peroxiredoxin function may increase stress resistance by reducing insulin secretion, but that further changes in insulin signalling are required for the reprogramming of development and fat metabolism. In addition, we reveal that the temperature-dependent prolongevity function of PRDX-2 is required for the extended lifespan associated with several pathways, including further reductions in IIS. PMID:25808059

  8. Comparative Endocrinology of Aging and Longevity Regulation

    PubMed Central

    Allard, John B.; Duan, Cunming

    2011-01-01

    Hormones regulate growth, development, metabolism, and other complex processes in multicellular animals. For many years it has been suggested that hormones may also influence the rate of the aging process. Aging is a multifactorial process that causes biological systems to break down and cease to function in adult organisms as time passes, eventually leading to death. The exact underlying causes of the aging process remain a topic for debate, and clues that may shed light on these causes are eagerly sought after. In the last two decades, gene mutations that result in delayed aging and extended longevity have been discovered, and many of the affected genes have been components of endocrine signaling pathways. In this review we summarize the current knowledge on the roles of endocrine signaling in the regulation of aging and longevity in various animals. We begin by discussing the notion that conserved systems, including endocrine signaling pathways, “regulate” the aging process. Findings from the major model organisms: worms, flies, and rodents, are then outlined. Unique lessons from studies of non-traditional models: bees, salmon, and naked mole rats, are also discussed. Finally, we summarize the endocrinology of aging in humans, including changes in hormone levels with age, and the involvement of hormones in aging-related diseases. The most well studied and widely conserved endocrine pathway that affects aging is the insulin/insulin-like growth factor system. Mutations in genes of this pathway increase the lifespan of worms, flies, and mice. Population genetic evidence also suggests this pathway’s involvement in human aging. Other hormones including steroids have been linked to aging only in a subset of the models studied. Because of the value of comparative studies, it is suggested that the aging field could benefit from adoption of additional model organisms. PMID:22654825

  9. Mood, stress and longevity: convergence on ANK3.

    PubMed

    Rangaraju, S; Levey, D F; Nho, K; Jain, N; Andrews, K D; Le-Niculescu, H; Salomon, D R; Saykin, A J; Petrascheck, M; Niculescu, A B

    2016-08-01

    Antidepressants have been shown to improve longevity in C. elegans. It is plausible that orthologs of genes involved in mood regulation and stress response are involved in such an effect. We sought to understand the underlying biology. First, we analyzed the transcriptome from worms treated with the antidepressant mianserin, previously identified in a large-scale unbiased drug screen as promoting increased lifespan in worms. We identified the most robust treatment-related changes in gene expression, and identified the corresponding human orthologs. Our analysis uncovered a series of genes and biological pathways that may be at the interface between antidepressant effects and longevity, notably pathways involved in drug metabolism/degradation (nicotine and melatonin). Second, we examined which of these genes overlap with genes which may be involved in depressive symptoms in an aging non-psychiatric human population (n=3577), discovered using a genome-wide association study (GWAS) approach in a design with extremes of distribution of phenotype. Third, we used a convergent functional genomics (CFG) approach to prioritize these genes for relevance to mood disorders and stress. The top gene identified was ANK3. To validate our findings, we conducted genetic and gene-expression studies, in C. elegans and in humans. We studied C. elegans inactivating mutants for ANK3/unc-44, and show that they survive longer than wild-type, particularly in older worms, independently of mianserin treatment. We also show that some ANK3/unc-44 expression is necessary for the effects of mianserin on prolonging lifespan and survival in the face of oxidative stress, particularly in younger worms. Wild-type ANK3/unc-44 increases in expression with age in C. elegans, and is maintained at lower youthful levels by mianserin treatment. These lower levels may be optimal in terms of longevity, offering a favorable balance between sufficient oxidative stress resistance in younger worms and survival

  10. Phosphatidylethanolamine positively regulates autophagy and longevity

    PubMed Central

    Rockenfeller, P; Koska, M; Pietrocola, F; Minois, N; Knittelfelder, O; Sica, V; Franz, J; Carmona-Gutierrez, D; Kroemer, G; Madeo, F

    2015-01-01

    Autophagy is a cellular recycling program that retards ageing by efficiently eliminating damaged and potentially harmful organelles and intracellular protein aggregates. Here, we show that the abundance of phosphatidylethanolamine (PE) positively regulates autophagy. Reduction of intracellular PE levels by knocking out either of the two yeast phosphatidylserine decarboxylases (PSD) accelerated chronological ageing-associated production of reactive oxygen species and death. Conversely, the artificial increase of intracellular PE levels, by provision of its precursor ethanolamine or by overexpression of the PE-generating enzyme Psd1, significantly increased autophagic flux, both in yeast and in mammalian cell culture. Importantly administration of ethanolamine was sufficient to extend the lifespan of yeast (Saccharomyces cerevisiae), mammalian cells (U2OS, H4) and flies (Drosophila melanogaster). We thus postulate that the availability of PE may constitute a bottleneck for functional autophagy and that organismal life or healthspan could be positively influenced by the consumption of ethanolamine-rich food. PMID:25571976

  11. Juvenile hormone regulation of longevity in the migratory monarch butterfly.

    PubMed

    Herman, W S; Tatar, M

    2001-12-22

    Monarch butterflies (Danaus plexippus) of eastern North America are well known for their long-range migration to overwintering roosts in south-central Mexico. An essential feature of this migration involves the exceptional longevity of the migrant adults; individuals persist from August/September to March while their summer counterparts are likely to live less than two months as adults. Migrant adults persist during a state of reproductive diapause in which both male and female reproductive development is arrested as a consequence of suppressed synthesis of juvenile hormone. Here, we describe survival in monarch butterflies as a function of the migrant syndrome. We show that migrant adults are longer lived than summer adults when each are maintained under standard laboratory conditions, that the longevity of migrant adults is curtailed by treatment with juvenile hormone and that the longevity of summer adults is increased by 100% when juvenile hormone synthesis is prevented by surgical removal of its source, the corpora allatum. Thus, monarch butterfly persistence through a long winter season is ensured in part by reduced ageing that is under endocrine regulation, as well as by the unique environmental properties of their winter roost sites. Phenotypic plasticity for ageing is an integral component of the monarch butterflies' migration-diapause syndrome. PMID:11749703

  12. Bacopa monnieri promotes longevity in Caenorhabditis elegans under stress conditions

    PubMed Central

    Phulara, Suresh C.; Shukla, Virendra; Tiwari, Sudeep; Pandey, Rakesh

    2015-01-01

    Background: Bacopa monnieri (L.) Pennell, commonly known as Brahmi is an important medicinal plant traditionally used as memory enhancer and antiepileptic agent. Objective: The present study investigated antioxidant and stress resistance potentials of B. monnieri aqueous extract (BMW) using Caenorhabditis elegans animal model system. Materials and Methods: The antioxidant activity of the BMW was measured using in vitro (DPPH, reducing power and total polyphenol content) and in vivo (DCF-DA assay) assays. The antistress potential of BMW (0.1, 0.01, and 0.001 mg/ml) was evaluated through thermal stress (37°C) and oxidative stress (10 mM paraquat) using C. elegans. Quantification of the HSP-16.2 level was done using CL2070 transgenic worms. Results: Present study reveals that BMW possess in vitro and in vivo antioxidant activities. BMW significantly enhanced stress tolerance and increased the mean lifespan of worms during thermal and oxidative stress, although it did not extend lifespan at 20°C and attenuated age dependent decline in physiological behaviors. Moreover, it was shown that BMW was able to up-regulate expression of stress associated gene hsp-16.2, which significantly (P < 0.001) extends the mean lifespan of worms under stress conditions. Conclusion: The study strongly suggests that BMW acts as an antistressor and potent reactive oxygen species scavenger which enhances the survival of the worms in different stress conditions. PMID:25829783

  13. Regulation of Nrf2 signaling and longevity in naturally long-lived rodents.

    PubMed

    Lewis, Kaitlyn N; Wason, Emily; Edrey, Yael H; Kristan, Deborah M; Nevo, Eviatar; Buffenstein, Rochelle

    2015-03-24

    The preternaturally long-lived naked mole-rat, like other long-lived species and experimental models of extended longevity, is resistant to both endogenous (e.g., reactive oxygen species) and environmental stressors and also resists age-related diseases such as cancer, cardiovascular disease, and neurodegeneration. The mechanisms behind the universal resilience of longer-lived organisms to stress, however, remain elusive. We hypothesize that this resilience is linked to the activity of a highly conserved transcription factor, nuclear factor erythroid 2-related factor (Nrf2). Nrf2 regulates the transcription of several hundred cytoprotective molecules, including antioxidants, detoxicants, and molecular chaperones (heat shock proteins). Nrf2 itself is tightly regulated by mechanisms that either promote its activity or increase its degradation. We used a comparative approach and examined Nrf2-signaling activity in naked mole-rats and nine other rodent species with varying maximum lifespan potential (MLSP). We found that constitutive Nrf2-signaling activity was positively correlated (P = 0.0285) with MLSP and that this activity was also manifested in high levels of downstream gene expression and activity. Surprisingly, we found that species longevity was not linked to the protein levels of Nrf2 itself, but rather showed a significant (P < 0.01) negative relationship with the regulators Kelch-like ECH-Associated Protein 1 (Keap1) and β-transducin repeat-containing protein (βTrCP), which target Nrf2 for degradation. These findings highlight the use of a comparative biology approach for the identification of evolved mechanisms that contribute to health span, aging, and longevity. PMID:25775529

  14. A Novel 3-Hydroxysteroid Dehydrogenase That Regulates Reproductive Development and Longevity

    PubMed Central

    Wollam, Joshua; Magner, Daniel B.; Magomedova, Lilia; Rass, Elisabeth; Shen, Yidong; Rottiers, Veerle; Habermann, Bianca; Cummins, Carolyn L.; Antebi, Adam

    2012-01-01

    Endogenous small molecule metabolites that regulate animal longevity are emerging as a novel means to influence health and life span. In C. elegans, bile acid-like steroids called the dafachronic acids (DAs) regulate developmental timing and longevity through the conserved nuclear hormone receptor DAF-12, a homolog of mammalian sterol-regulated receptors LXR and FXR. Using metabolic genetics, mass spectrometry, and biochemical approaches, we identify new activities in DA biosynthesis and characterize an evolutionarily conserved short chain dehydrogenase, DHS-16, as a novel 3-hydroxysteroid dehydrogenase. Through regulation of DA production, DHS-16 controls DAF-12 activity governing longevity in response to signals from the gonad. Our elucidation of C. elegans bile acid biosynthetic pathways reveals the possibility of novel ligands as well as striking biochemical conservation to other animals, which could illuminate new targets for manipulating longevity in metazoans. PMID:22505847

  15. Aging. Lysosomal signaling molecules regulate longevity in Caenorhabditis elegans.

    PubMed

    Folick, Andrew; Oakley, Holly D; Yu, Yong; Armstrong, Eric H; Kumari, Manju; Sanor, Lucas; Moore, David D; Ortlund, Eric A; Zechner, Rudolf; Wang, Meng C

    2015-01-01

    Lysosomes are crucial cellular organelles for human health that function in digestion and recycling of extracellular and intracellular macromolecules. We describe a signaling role for lysosomes that affects aging. In the worm Caenorhabditis elegans, the lysosomal acid lipase LIPL-4 triggered nuclear translocalization of a lysosomal lipid chaperone LBP-8, which promoted longevity by activating the nuclear hormone receptors NHR-49 and NHR-80. We used high-throughput metabolomic analysis to identify several lipids in which abundance was increased in worms constitutively overexpressing LIPL-4. Among them, oleoylethanolamide directly bound to LBP-8 and NHR-80 proteins, activated transcription of target genes of NHR-49 and NHR-80, and promoted longevity in C. elegans. These findings reveal a lysosome-to-nucleus signaling pathway that promotes longevity and suggest a function of lysosomes as signaling organelles in metazoans. PMID:25554789

  16. Feedback regulation via AMPK and HIF-1 mediates ROS-dependent longevity in Caenorhabditis elegans

    PubMed Central

    Hwang, Ara B.; Ryu, Eun-A; Artan, Murat; Chang, Hsin-Wen; Kabir, Mohammad Humayun; Nam, Hyun-Jun; Lee, Dongyeop; Yang, Jae-Seong; Kim, Sanguk; Mair, William B.; Lee, Cheolju; Lee, Siu Sylvia; Lee, Seung-Jae

    2014-01-01

    Mild inhibition of mitochondrial respiration extends the lifespan of many species. In Caenorhabditis elegans, reactive oxygen species (ROS) promote longevity by activating hypoxia-inducible factor 1 (HIF-1) in response to reduced mitochondrial respiration. However, the physiological role and mechanism of ROS-induced longevity are poorly understood. Here, we show that a modest increase in ROS increases the immunity and lifespan of C. elegans through feedback regulation by HIF-1 and AMP-activated protein kinase (AMPK). We found that activation of AMPK as well as HIF-1 mediates the longevity response to ROS. We further showed that AMPK reduces internal levels of ROS, whereas HIF-1 amplifies the levels of internal ROS under conditions that increase ROS. Moreover, mitochondrial ROS increase resistance to various pathogenic bacteria, suggesting a possible association between immunity and long lifespan. Thus, AMPK and HIF-1 may control immunity and longevity tightly by acting as feedback regulators of ROS. PMID:25288734

  17. Mondo complexes regulate TFEB via TOR inhibition to promote longevity in response to gonadal signals

    PubMed Central

    Nakamura, Shuhei; Karalay, Özlem; Jäger, Philipp S.; Horikawa, Makoto; Klein, Corinna; Nakamura, Kayo; Latza, Christian; Templer, Sven E.; Dieterich, Christoph; Antebi, Adam

    2016-01-01

    Germline removal provokes longevity in several species and shifts resources towards survival and repair. Several Caenorhabditis elegans transcription factors regulate longevity arising from germline removal; yet, how they work together is unknown. Here we identify a Myc-like HLH transcription factor network comprised of Mondo/Max-like complex (MML-1/MXL-2) to be required for longevity induced by germline removal, as well as by reduced TOR, insulin/IGF signalling and mitochondrial function. Germline removal increases MML-1 nuclear accumulation and activity. Surprisingly, MML-1 regulates nuclear localization and activity of HLH-30/TFEB, a convergent regulator of autophagy, lysosome biogenesis and longevity, by downregulating TOR signalling via LARS-1/leucyl-transfer RNA synthase. HLH-30 also upregulates MML-1 upon germline removal. Mammalian MondoA/B and TFEB show similar mutual regulation. MML-1/MXL-2 and HLH-30 transcriptomes show both shared and preferential outputs including MDL-1/MAD-like HLH factor required for longevity. These studies reveal how an extensive interdependent HLH transcription factor network distributes responsibility and mutually enforces states geared towards reproduction or survival. PMID:27001890

  18. Mondo complexes regulate TFEB via TOR inhibition to promote longevity in response to gonadal signals.

    PubMed

    Nakamura, Shuhei; Karalay, Özlem; Jäger, Philipp S; Horikawa, Makoto; Klein, Corinna; Nakamura, Kayo; Latza, Christian; Templer, Sven E; Dieterich, Christoph; Antebi, Adam

    2016-01-01

    Germline removal provokes longevity in several species and shifts resources towards survival and repair. Several Caenorhabditis elegans transcription factors regulate longevity arising from germline removal; yet, how they work together is unknown. Here we identify a Myc-like HLH transcription factor network comprised of Mondo/Max-like complex (MML-1/MXL-2) to be required for longevity induced by germline removal, as well as by reduced TOR, insulin/IGF signalling and mitochondrial function. Germline removal increases MML-1 nuclear accumulation and activity. Surprisingly, MML-1 regulates nuclear localization and activity of HLH-30/TFEB, a convergent regulator of autophagy, lysosome biogenesis and longevity, by downregulating TOR signalling via LARS-1/leucyl-transfer RNA synthase. HLH-30 also upregulates MML-1 upon germline removal. Mammalian MondoA/B and TFEB show similar mutual regulation. MML-1/MXL-2 and HLH-30 transcriptomes show both shared and preferential outputs including MDL-1/MAD-like HLH factor required for longevity. These studies reveal how an extensive interdependent HLH transcription factor network distributes responsibility and mutually enforces states geared towards reproduction or survival. PMID:27001890

  19. Specioside ameliorates oxidative stress and promotes longevity in Caenorhabditis elegans.

    PubMed

    Asthana, Jyotsna; Yadav, A K; Pant, Aakanksha; Pandey, Swapnil; Gupta, M M; Pandey, Rakesh

    2015-03-01

    Specioside (6-O-coumaroylcatalpol) is an iridoid glucoside which possesses multifunctional activities viz. analgesic, antidyspeptic, astringent, liver stimulating and wound healing properties. The present study for the first time delineates stress alleviating and lifespan prolonging action of specioside (SPC), isolated from Stereospermum suaveolens in the free living, multicellular nematode model Caenorhabditis elegans. A strong correlation between lifespan extension and stress modulation in adult worms was established in a dose dependent manner. The dietary intake of this phytomolecule elevated juglone induced oxidative and heat induced thermal stress tolerance in C. elegans. On evaluation, it was found that 25 μM dose of SPC significantly extended lifespan by 15.47% (P≤0.0001) with reduction in stress level. Furthermore, SPC enhanced mean survival in mev-1 mutant suggesting its oxidative stress reducing potential. Furthermore, SPC augmented stress modulatory enzymes superoxide dismutase (SOD) and catalase (CAT) level in C. elegans. Altogether, these findings broaden current perspectives concerning stress alleviating potentials of SPC and have implications in development of therapeutics for curing age related disorders. PMID:25619942

  20. Skeletal muscle as a regulator of the longevity protein, Klotho

    PubMed Central

    Avin, Keith G.; Coen, Paul M.; Huang, Wan; Stolz, Donna B.; Sowa, Gwendolyn A.; Dubé, John J.; Goodpaster, Bret H.; O'Doherty, Robert M.; Ambrosio, Fabrisia

    2014-01-01

    Klotho is a powerful longevity protein that has been linked to the prevention of muscle atrophy, osteopenia, and cardiovascular disease. Similar anti-aging effects have also been ascribed to exercise and physical activity. While an association between muscle function and Klotho expression has been previously suggested from longitudinal cohort studies, a direct relationship between circulating Klotho and skeletal muscle has not been investigated. In this paper, we present a review of the literature and preliminary evidence that, together, suggests Klotho expression may be modulated by skeletal muscle activity. Our pilot clinical findings performed in young and aged individuals suggest that circulating Klotho levels are upregulated in response to an acute exercise bout, but that the response may be dependent on fitness level. A similar upregulation of circulating Klotho is also observed in response to an acute exercise in young and old mice, suggesting that this may be a good model for mechanistically probing the role of physical activity on Klotho expression. Finally, we highlight overlapping signaling pathways that are modulated by both Klotho and skeletal muscle and propose potential mechanisms for cross-talk between the two. It is hoped that this review will stimulate further consideration of the relationship between skeletal muscle activity and Klotho expression, potentially leading to important insights into the well-documented systemic anti-aging effects of exercise. PMID:24987372

  1. Inactivation of yeast Isw2 chromatin remodeling enzyme mimics longevity effect of calorie restriction via induction of genotoxic stress response

    PubMed Central

    Dang, Weiwei; Sutphin, George L.; Dorsey, Jean A.; Otte, Gabriel L.; Cao, Kajia; Perry, Rocco M.; Wanat, Jennifer J.; Saviolaki, Dimitra; Murakami, Christopher J.; Tsuchiyama, Scott; Robison, Brett; Gregory, Brian D.; Vermeulen, Michiel; Shiekhattar, Ramin; Johnson, F. Brad; Kennedy, Brian K.; Kaeberlein, Matt; Berger, Shelley L.

    2014-01-01

    Summary ATP-dependent chromatin remodeling is involved in all DNA transactions and linked to numerous human diseases. We explored functions of chromatin remodelers during cellular aging. Deletion of ISW2, or mutations inactivating the Isw2 enzyme complex, extends yeast replicative lifespan. This extension by ISW2 deletion is epistatic to the longevity effect of calorie restriction (CR) and this mechanism is distinct from suppression of TOR signaling by CR. Transcriptome analysis indicates that isw2Δ partially mimics an up-regulated stress response in CR cells. In particular, isw2Δ cells show an increased response to genotoxic stresses, and the DNA repair enzyme Rad51 is important for isw2Δ-mediated longevity. We show that lifespan is also extended in C. elegans by reducing levels of athp-2, a putative ortholog of Itc1/ACF1, a critical subunit of the enzyme complex. Our findings demonstrate that the ISWI class of ATP-dependent chromatin remodeling complexes play a conserved role during aging and in calorie restriction. PMID:24814484

  2. Stress responses, vitagenes and hormesis as critical determinants in aging and longevity: Mitochondria as a “chi”

    PubMed Central

    2013-01-01

    Understanding mechanisms of aging and determinants of life span will help to reduce age-related morbidity and facilitate healthy aging. Average lifespan has increased over the last centuries, as a consequence of medical and environmental factors, but maximal life span remains unchanged. Extension of maximal life span is currently possible in animal models with measures such as genetic manipulations and caloric restriction (CR). CR appears to prolong life by reducing reactive oxygen species (ROS)-mediated oxidative damage. But ROS formation, which is positively implicated in cellular stress response mechanisms, is a highly regulated process controlled by a complex network of intracellular signaling pathways. By sensing the intracellular nutrient and energy status, the functional state of mitochondria, and the concentration of ROS produced in mitochondria, the longevity network regulates life span across species by coordinating information flow along its convergent, divergent and multiply branched signaling pathways, including vitagenes which are genes involved in preserving cellular homeostasis during stressful conditions. Vitagenes encode for heat shock proteins (Hsp) Hsp32, Hsp70, the thioredoxin and the sirtuin protein systems. Dietary antioxidants, have recently been demonstrated to be neuroprotective through the activation of hormetic pathways, including vitagenes. The hormetic dose–response, challenges long-standing beliefs about the nature of the dose–response in a lowdose zone, having the potential to affect significantly the design of pre-clinical studies and clinical trials as well as strategies for optimal patient dosing in the treatment of numerous diseases. Given the broad cytoprotective properties of the heat shock response there is now strong interest in discovering and developing pharmacological agents capable of inducing stress responses. Here we focus on possible signaling mechanisms involved in the activation of vitagenes resulting in enhanced

  3. Longevity extension by phytochemicals.

    PubMed

    Leonov, Anna; Arlia-Ciommo, Anthony; Piano, Amanda; Svistkova, Veronika; Lutchman, Vicky; Medkour, Younes; Titorenko, Vladimir I

    2015-01-01

    Phytochemicals are structurally diverse secondary metabolites synthesized by plants and also by non-pathogenic endophytic microorganisms living within plants. Phytochemicals help plants to survive environmental stresses, protect plants from microbial infections and environmental pollutants, provide them with a defense from herbivorous organisms and attract natural predators of such organisms, as well as lure pollinators and other symbiotes of these plants. In addition, many phytochemicals can extend longevity in heterotrophic organisms across phyla via evolutionarily conserved mechanisms. In this review, we discuss such mechanisms. We outline how structurally diverse phytochemicals modulate a complex network of signaling pathways that orchestrate a distinct set of longevity-defining cellular processes. This review also reflects on how the release of phytochemicals by plants into a natural ecosystem may create selective forces that drive the evolution of longevity regulation mechanisms in heterotrophic organisms inhabiting this ecosystem. We outline the most important unanswered questions and directions for future research in this vibrant and rapidly evolving field. PMID:25871373

  4. A Genetic Network Associated With Stress Resistance, Longevity, and Cancer in Humans.

    PubMed

    Levine, Morgan E; Crimmins, Eileen M

    2016-06-01

    Human longevity and diseases are likely influenced by multiple interacting genes within a few biologically conserved pathways. Using long-lived smokers as a phenotype (n = 90)-a group whose survival may signify innate resilience-we conducted a genome-wide association study comparing them to smokers at ages 52-69 (n = 730). These results were used to conduct a functional interaction network and pathway analysis, to identify single nucleotide polymorphisms that collectively related to smokers' longevity. We identified a set of 215 single nucleotide polymorphisms (all of which had p <5×10(-3) in the genome-wide association study) that were located within genes making-up a functional interaction network. These single nucleotide polymorphisms were then used to create a weighted polygenic risk score that, using an independent validation sample of nonsmokers (N = 6,447), was found to be significantly associated with a 22% increase in the likelihood of being aged 90-99 (n = 253) and an over threefold increase in the likelihood of being a centenarian (n = 4), compared with being at ages 52-79 (n = 4,900). Additionally, the polygenic risk score was also associated with an 11% reduction in cancer prevalence over up to 18 years (odds ratio: 0.89, p = .011). Overall, using a unique phenotype and incorporating prior knowledge of biological networks, this study identified a set of single nucleotide polymorphisms that together appear to be important for human aging, stress resistance, cancer, and longevity. PMID:26355015

  5. Longevity of animals under reactive oxygen species stress and disease susceptibility due to global warming.

    PubMed

    Paital, Biswaranjan; Panda, Sumana Kumari; Hati, Akshaya Kumar; Mohanty, Bobllina; Mohapatra, Manoj Kumar; Kanungo, Shyama; Chainy, Gagan Bihari Nityananda

    2016-02-26

    The world is projected to experience an approximate doubling of atmospheric CO2 concentration in the next decades. Rise in atmospheric CO2 level as one of the most important reasons is expected to contribute to raise the mean global temperature 1.4 °C-5.8 °C by that time. A survey from 128 countries speculates that global warming is primarily due to increase in atmospheric CO2 level that is produced mainly by anthropogenic activities. Exposure of animals to high environmental temperatures is mostly accompanied by unwanted acceleration of certain biochemical pathways in their cells. One of such examples is augmentation in generation of reactive oxygen species (ROS) and subsequent increase in oxidation of lipids, proteins and nucleic acids by ROS. Increase in oxidation of biomolecules leads to a state called as oxidative stress (OS). Finally, the increase in OS condition induces abnormality in physiology of animals under elevated temperature. Exposure of animals to rise in habitat temperature is found to boost the metabolism of animals and a very strong and positive correlation exists between metabolism and levels of ROS and OS. Continuous induction of OS is negatively correlated with survivability and longevity and positively correlated with ageing in animals. Thus, it can be predicted that continuous exposure of animals to acute or gradual rise in habitat temperature due to global warming may induce OS, reduced survivability and longevity in animals in general and poikilotherms in particular. A positive correlation between metabolism and temperature in general and altered O2 consumption at elevated temperature in particular could also increase the risk of experiencing OS in homeotherms. Effects of global warming on longevity of animals through increased risk of protein misfolding and disease susceptibility due to OS as the cause or effects or both also cannot be ignored. Therefore, understanding the physiological impacts of global warming in relation to

  6. Longevity of animals under reactive oxygen species stress and disease susceptibility due to global warming

    PubMed Central

    Paital, Biswaranjan; Panda, Sumana Kumari; Hati, Akshaya Kumar; Mohanty, Bobllina; Mohapatra, Manoj Kumar; Kanungo, Shyama; Chainy, Gagan Bihari Nityananda

    2016-01-01

    The world is projected to experience an approximate doubling of atmospheric CO2 concentration in the next decades. Rise in atmospheric CO2 level as one of the most important reasons is expected to contribute to raise the mean global temperature 1.4 °C-5.8 °C by that time. A survey from 128 countries speculates that global warming is primarily due to increase in atmospheric CO2 level that is produced mainly by anthropogenic activities. Exposure of animals to high environmental temperatures is mostly accompanied by unwanted acceleration of certain biochemical pathways in their cells. One of such examples is augmentation in generation of reactive oxygen species (ROS) and subsequent increase in oxidation of lipids, proteins and nucleic acids by ROS. Increase in oxidation of biomolecules leads to a state called as oxidative stress (OS). Finally, the increase in OS condition induces abnormality in physiology of animals under elevated temperature. Exposure of animals to rise in habitat temperature is found to boost the metabolism of animals and a very strong and positive correlation exists between metabolism and levels of ROS and OS. Continuous induction of OS is negatively correlated with survivability and longevity and positively correlated with ageing in animals. Thus, it can be predicted that continuous exposure of animals to acute or gradual rise in habitat temperature due to global warming may induce OS, reduced survivability and longevity in animals in general and poikilotherms in particular. A positive correlation between metabolism and temperature in general and altered O2 consumption at elevated temperature in particular could also increase the risk of experiencing OS in homeotherms. Effects of global warming on longevity of animals through increased risk of protein misfolding and disease susceptibility due to OS as the cause or effects or both also cannot be ignored. Therefore, understanding the physiological impacts of global warming in relation to

  7. Chronic stress alters the expression levels of longevity-related genes in the rat hippocampus.

    PubMed

    Sánchez-Hidalgo, Ana C; Muñoz, Mario F; Herrera, Antonio J; Espinosa-Oliva, Ana M; Stowell, Rianne; Ayala, Antonio; Machado, Alberto; Venero, José L; de Pablos, Rocío M

    2016-07-01

    The molecular mechanisms underlying the negative effects of psychological stress on cellular stress during aging and neurodegenerative diseases are poorly understood. The main objective of this study was to test the effect of chronic psychological stress, and the consequent increase of circulating glucocorticoids, on several hippocampal genes involved in longevity. Sirtuin-1, p53, thioredoxin-interacting protein, and heat shock protein 70 were studied at the mRNA and protein levels in stressed and non-stressed animals. Stress treatment for 10 days decreased sirtuin-1 and heat shock protein 70 levels, but increased levels of p53, thioredoxin-interacting protein and the NADPH oxidase enzyme. Examination of protein expression following two months of stress treatment indicated that sirtuin-1 remained depressed. In contrast, an increase was observed for thioredoxin-interacting protein, heat shock protein 70, p53 and the NADPH oxidase enzyme. The effect of stress was reversed by mifepristone, a glucocorticoid receptor antagonist. These data suggest that chronic stress could contribute to aging in the hippocampus. PMID:27120255

  8. The GATA transcription factor/MTA-1 homolog egr-1 promotes longevity and stress resistance in Caenorhabditis elegans

    PubMed Central

    Zimmerman, Stephanie M; Kim, Stuart K

    2014-01-01

    Aging is associated with a large number of both phenotypic and molecular changes, but for most of these, it is not known whether these changes are detrimental, neutral, or protective. We have identified a conserved Caenorhabditis elegans GATA transcription factor/MTA-1 homolog egr-1 (lin-40) that extends lifespan and promotes resistance to heat and UV stress when overexpressed. Expression of egr-1 increases with age, suggesting that it may promote survival during normal aging. This increase in expression is dependent on the presence of the germline, raising the possibility that egr-1 expression is regulated by signals from the germline. In addition, loss of egr-1 suppresses the long lifespan of insulin receptor daf-2 mutants. The DAF-16 FOXO transcription factor is required for the increased stress resistance of egr-1 overexpression mutants, and egr-1 is necessary for the proper regulation of sod-3 (a reporter for DAF-16 activity). These results indicate that egr-1 acts within the insulin signaling pathway. egr-1 can also activate the expression of its paralog egl-27, another factor known to extend lifespan and increase stress resistance, suggesting that the two genes act in a common program to promote survival. These results identify egr-1 as part of a longevity-promoting circuit that changes with age in a manner that is beneficial for the lifespan of the organism. PMID:24304470

  9. TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO.

    PubMed

    Robida-Stubbs, Stacey; Glover-Cutter, Kira; Lamming, Dudley W; Mizunuma, Masaki; Narasimhan, Sri Devi; Neumann-Haefelin, Elke; Sabatini, David M; Blackwell, T Keith

    2012-05-01

    The TOR kinase, which is present in the functionally distinct complexes TORC1 and TORC2, is essential for growth but associated with disease and aging. Elucidation of how TOR influences life span will identify mechanisms of fundamental importance in aging and TOR functions. Here we show that when TORC1 is inhibited genetically in C. elegans, SKN-1/Nrf, and DAF-16/FoxO activate protective genes, and increase stress resistance and longevity. SKN-1 also upregulates TORC1 pathway gene expression in a feedback loop. Rapamycin triggers a similar protective response in C. elegans and mice, but increases worm life span dependent upon SKN-1 and not DAF-16, apparently by interfering with TORC2 along with TORC1. TORC1, TORC2, and insulin/IGF-1-like signaling regulate SKN-1 activity through different mechanisms. We conclude that modulation of SKN-1/Nrf and DAF-16/FoxO may be generally important in the effects of TOR signaling in vivo and that these transcription factors mediate an opposing relationship between growth signals and longevity. PMID:22560223

  10. Homeodomain-Interacting Protein Kinase (HPK-1) regulates stress responses and ageing in C. elegans

    PubMed Central

    Berber, Slavica; Wood, Mallory; Llamosas, Estelle; Thaivalappil, Priya; Lee, Karen; Liao, Bing Mana; Chew, Yee Lian; Rhodes, Aaron; Yucel, Duygu; Crossley, Merlin; Nicholas, Hannah R

    2016-01-01

    Proteins of the Homeodomain-Interacting Protein Kinase (HIPK) family regulate an array of processes in mammalian systems, such as the DNA damage response, cellular proliferation and apoptosis. The nematode Caenorhabditis elegans has a single HIPK homologue called HPK-1. Previous studies have implicated HPK-1 in longevity control and suggested that this protein may be regulated in a stress-dependent manner. Here we set out to expand these observations by investigating the role of HPK-1 in longevity and in the response to heat and oxidative stress. We find that levels of HPK-1 are regulated by heat stress, and that HPK-1 contributes to survival following heat or oxidative stress. Additionally, we show that HPK-1 is required for normal longevity, with loss of HPK-1 function leading to a faster decline of physiological processes that reflect premature ageing. Through microarray analysis, we have found that HPK-1-regulated genes include those encoding proteins that serve important functions in stress responses such as Phase I and Phase II detoxification enzymes. Consistent with a role in longevity assurance, HPK-1 also regulates the expression of age-regulated genes. Lastly, we show that HPK-1 functions in the same pathway as DAF-16 to regulate longevity and reveal a new role for HPK-1 in development. PMID:26791749

  11. A chromatin modifier integrates insulin/IGF-1 signalling and dietary restriction to regulate longevity.

    PubMed

    Singh, Anupama; Kumar, Neeraj; Matai, Latika; Jain, Vaibhav; Garg, Amit; Mukhopadhyay, Arnab

    2016-08-01

    Insulin/IGF-1-like signalling (IIS) and dietary restriction (DR) are the two major modulatory pathways controlling longevity across species. Here, we show that both pathways license a common chromatin modifier, ZFP-1/AF10. The downstream transcription factors of the IIS and select DR pathways, DAF-16/FOXO or PHA-4/FOXA, respectively, both transcriptionally regulate the expression of zfp-1. ZFP-1, in turn, negatively regulates the expression of DAF-16/FOXO and PHA-4/FOXA target genes, apparently forming feed-forward loops that control the amplitude as well as the duration of gene expression. We show that ZFP-1 mediates this regulation by negatively influencing the recruitment of DAF-16/FOXO and PHA-4/FOXA to their target promoters. Consequently, zfp-1 is required for the enhanced longevity observed during DR and on knockdown of IIS. Our data reveal how two distinct sensor pathways control an overlapping set of genes, using different downstream transcription factors, integrating potentially diverse and temporally distinct nutritional situations. PMID:27039057

  12. Genes down-regulated in spaceflight are involved in the control of longevity in Caenorhabditis elegans

    PubMed Central

    Honda, Yoko; Higashibata, Akira; Matsunaga, Yohei; Yonezawa, Yukiko; Kawano, Tsuyoshi; Higashitani, Atsushi; Kuriyama, Kana; Shimazu, Toru; Tanaka, Masashi; Szewczyk, Nathaniel J.; Ishioka, Noriaki; Honda, Shuji

    2012-01-01

    How microgravitational space environments affect aging is not well understood. We observed that, in Caenorhabditis elegans, spaceflight suppressed the formation of transgenically expressed polyglutamine aggregates, which normally accumulate with increasing age. Moreover, the inactivation of each of seven genes that were down-regulated in space extended lifespan on the ground. These genes encode proteins that are likely related to neuronal or endocrine signaling: acetylcholine receptor, acetylcholine transporter, choline acetyltransferase, rhodopsin-like receptor, glutamate-gated chloride channel, shaker family of potassium channel, and insulin-like peptide. Most of them mediated lifespan control through the key longevity-regulating transcription factors DAF-16 or SKN-1 or through dietary-restriction signaling, singly or in combination. These results suggest that aging in C. elegans is slowed through neuronal and endocrine response to space environmental cues. PMID:22768380

  13. Folic acid supplementation at lower doses increases oxidative stress resistance and longevity in Caenorhabditis elegans.

    PubMed

    Rathor, Laxmi; Akhoon, Bashir Akhlaq; Pandey, Swapnil; Srivastava, Swati; Pandey, Rakesh

    2015-12-01

    Folic acid (FA) is an essential nutrient that the human body needs but cannot be synthesized on its own. Fortified foods and plant food sources such as green leafy vegetables, beans, fruits, and juices are good sources of FA to meet the daily requirements of the body. The aim was to evaluate the effect of dietary FA levels on the longevity of well-known experimental aging model Caenorhabditis elegans. Here, we show for first time that FA extends organism life span and causes a delay in aging. We observed that FA inhibits mechanistic target of rapamycin (mTOR) and insulin/insulin growth factor 1 (IGF-1) signaling pathways to control both oxidative stress levels and life span. The expression levels of stress- and life span-relevant gerontogenes, viz. daf-16, skn-1, and sir. 2.1, and oxidative enzymes, such as glutathione S-transferase 4 (GST-4) and superoxide dismutase 3 (SOD-3), were also found to be highly enhanced to attenuate the intracellular reactive oxygen species (ROS) damage and to delay the aging process. Our study promotes the use of FA to mitigate abiotic stresses and other aging-related ailments. PMID:26546011

  14. m:Explorer: multinomial regression models reveal positive and negative regulators of longevity in yeast quiescence

    PubMed Central

    2012-01-01

    We developed m:Explorer for identifying process-specific transcription factors (TFs) from multiple genome-wide sources, including transcriptome, DNA-binding and chromatin data. m:Explorer robustly outperforms similar techniques in finding cell cycle TFs in Saccharomyces cerevisiae. We predicted and experimentally tested regulators of quiescence (G0), a model of ageing, over a six-week time-course. We validated nine of top-12 predictions as novel G0 TFs, including Δmga2, Δcst6, Δbas1 with higher viability and G0-essential TFs Tup1, Swi3. Pathway analysis associates longevity to reduced growth, reprogrammed metabolism and cell wall remodeling. m:Explorer (http://biit.cs.ut.ee/mexplorer/) is instrumental in interrogating eukaryotic regulatory systems using heterogeneous data. PMID:22720667

  15. Sch9 regulates intracellular protein ubiquitination by controlling stress responses.

    PubMed

    Qie, Beibei; Lyu, Zhou; Lyu, Lei; Liu, Jun; Gao, Xuejie; Liu, Yanyan; Duan, Wei; Zhang, Nianhui; Du, Linfang; Liu, Ke

    2015-08-01

    Protein ubiquitination and the subsequent degradation are important means by which aberrant proteins are removed from cells, a key requirement for long-term survival. In this study, we found that the overall level of ubiquitinated proteins dramatically decreased as yeast cell grew from log to stationary phase. Deletion of SCH9, a gene encoding a key protein kinase for longevity control, decreased the level of ubiquitinated proteins in log phase and this effect could be reversed by restoring Sch9 function. We demonstrate here that the decrease of ubiquitinated proteins in sch9Δ cells in log phase is not caused by changes in ubiquitin expression, proteasome activity, or autophagy, but by enhanced expression of stress response factors and a decreased level of oxidative stress. Our results revealed for the first time how Sch9 regulates the level of ubiquitinated proteins and provides new insight into how Sch9 controls longevity. PMID:26087116

  16. Sch9 regulates intracellular protein ubiquitination by controlling stress responses

    PubMed Central

    Qie, Beibei; Lyu, Zhou; Lyu, Lei; Liu, Jun; Gao, Xuejie; Liu, Yanyan; Duan, Wei; Zhang, Nianhui; Du, Linfang; Liu, Ke

    2015-01-01

    Protein ubiquitination and the subsequent degradation are important means by which aberrant proteins are removed from cells, a key requirement for long-term survival. In this study, we found that the overall level of ubiquitinated proteins dramatically decreased as yeast cell grew from log to stationary phase. Deletion of SCH9, a gene encoding a key protein kinase for longevity control, decreased the level of ubiquitinated proteins in log phase and this effect could be reversed by restoring Sch9 function. We demonstrate here that the decrease of ubiquitinated proteins in sch9Δ cells in log phase is not caused by changes in ubiquitin expression, proteasome activity, or autophagy, but by enhanced expression of stress response factors and a decreased level of oxidative stress. Our results revealed for the first time how Sch9 regulates the level of ubiquitinated proteins and provides new insight into how Sch9 controls longevity. PMID:26087116

  17. Positive selection of Caenorhabditis elegans mutants with increased stress resistance and longevity.

    PubMed

    Muñoz, Manuel J; Riddle, Donald L

    2003-01-01

    We developed selective conditions for long-lived mutants of the nematode Caenorhabditis elegans by subjecting the first larval stage (L1) to thermal stress at 30 degrees for 7 days. The surviving larvae developed to fertile adults after the temperature was shifted to 15 degrees. A total of one million F(2) progeny and a half million F(3) progeny of ethyl-methanesulfonate-mutagenized animals were treated in three separate experiments. Among the 81 putative mutants that recovered and matured to the reproductive adult, 63 retested as thermotolerant and 49 (80%) exhibited a >15% increase in mean life span. All the known classes of dauer formation (Daf) mutant that affect longevity were found, including six new alleles of daf-2, and a unique temperature-sensitive, dauer-constitutive allele of age-1. Alleles of dyf-2 and unc-13 were isolated, and mutants of unc-18, a gene that interacts with unc-13, were also found to be long lived. Thirteen additional mutations define at least four new genes. PMID:12586705

  18. Trade-offs between survival, longevity, and reproduction, and variation of survival tolerance in Mediterranean Bemisia tabaci after temperature stress.

    PubMed

    Lü, Zhi-Chuang; Wang, Yan-Min; Zhu, Shao-Guang; Yu, Hao; Guo, Jian-Ying; Wan, Fang-Hao

    2014-01-01

    The invasive Mediterranean Bemisia tabaci (Gennadius) (Hemiptera: Aleyrodidae) has emerged as one of the most common agricultural pests in the world. In the present study, we examined the cross-tolerance, fitness costs, and benefits of thermal tolerance and the variation in the responses of life history traits after heat-shock selection. The results showed that survival and longevity of Mediterranean B. tabaci were decreased significantly after direct or cross temperature stress and that the number of eggs per female was not reduced significantly. Furthermore, heat-shock selection dramatically increased the survival of Mediterranean B. tabaci within two generations, and it did not significantly affect the egg number per female within five generations. These results indicated that there was a trade-off between survival, longevity, and reproduction in Mediterranean B. tabaci after temperature stress. The improvement in reproduction was costly in terms of decreased survival and longevity, and there was a fitness consequence to temperature stress. In addition, heat tolerance in Mediterranean B. tabaci increased substantially after selection by heat shock, indicating a considerable variation for survival tolerance in this species. This information could help us better understand the thermal biology of Mediterranean B. tabaci within the context of climate change. PMID:25368068

  19. AMPK and HIF signaling pathways regulate both longevity and cancer growth: the good news and the bad news about survival mechanisms.

    PubMed

    Salminen, Antero; Kaarniranta, Kai; Kauppinen, Anu

    2016-08-01

    The AMP-activated protein kinase (AMPK) and hypoxia-inducible factor (HIF) signaling pathways are evolutionarily-conserved survival mechanisms responding to two fundamental stresses, energy deficiency and/or oxygen deprivation. The AMPK and HIF pathways regulate the function of a survival network with several transcription factors, e.g. FOXO, NF-κB, NRF2, and p53, as well as with protein kinases and other factors, such as mTOR, ULK1, HDAC5, and SIRT1. Given that AMPK and HIF activation can enhance not only healthspan and lifespan but also cancer growth in a context-dependent manner; it seems that cancer cells can hijack certain survival factors to maintain their growth in harsh conditions. AMPK activation improves energy metabolism, stimulates autophagy, and inhibits inflammation, whereas HIF-1α increases angiogenesis and helps cells to adapt to severe conditions. First we will review how AMPK and HIF signaling mechanisms control the function of an integrated survival network which is able not only to improve the regulation of longevity but also support the progression of tumorigenesis. We will also describe distinct crossroads between the regulation of longevity and cancer, e.g. specific regulation through the AMPKα and HIF-α isoforms, the Warburg effect, mitochondrial dynamics, and cellular senescence. PMID:27259535

  20. Cellular stress response: a novel target for chemoprevention and nutritional neuroprotection in aging, neurodegenerative disorders and longevity.

    PubMed

    Calabrese, Vittorio; Cornelius, Carolin; Mancuso, Cesare; Pennisi, Giovanni; Calafato, Stella; Bellia, Francesco; Bates, Timothy E; Giuffrida Stella, Anna Maria; Schapira, Tony; Dinkova Kostova, Albena T; Rizzarelli, Enrico

    2008-12-01

    The predominant molecular symptom of aging is the accumulation of altered gene products. Moreover, several conditions including protein, lipid or glucose oxidation disrupt redox homeostasis and lead to accumulation of unfolded or misfolded proteins in the aging brain. Alzheimer's and Parkinson's diseases or Friedreich ataxia are neurological diseases sharing, as a common denominator, production of abnormal proteins, mitochondrial dysfunction and oxidative stress, which contribute to the pathogenesis of these so called "protein conformational diseases". The central nervous system has evolved the conserved mechanism of unfolded protein response to cope with the accumulation of misfolded proteins. As one of the main intracellular redox systems involved in neuroprotection, the vitagene system is emerging as a neurohormetic potential target for novel cytoprotective interventions. Vitagenes encode for cytoprotective heat shock proteins (Hsp) Hsp70 and heme oxygenase-1, as well as thioredoxin reductase and sirtuins. Nutritional studies show that ageing in animals can be significantly influenced by dietary restriction. Thus, the impact of dietary factors on health and longevity is an increasingly appreciated area of research. Reducing energy intake by controlled caloric restriction or intermittent fasting increases lifespan and protects various tissues against disease. Genetics has revealed that ageing may be controlled by changes in intracellular NAD/NADH ratio regulating sirtuin, a group of proteins linked to aging, metabolism and stress tolerance in several organisms. Recent findings suggest that several phytochemicals exhibit biphasic dose responses on cells with low doses activating signaling pathways that result in increased expression of vitagenes encoding survival proteins, as in the case of the Keap1/Nrf2/ARE pathway activated by curcumin and NAD/NADH-sirtuin-1 activated by resveratrol. Consistently, the neuroprotective roles of dietary antioxidants including

  1. Roles of the Developmental Regulator unc-62/Homothorax in Limiting Longevity in Caenorhabditis elegans

    PubMed Central

    Van Nostrand, Eric L.; Sánchez-Blanco, Adolfo; Wu, Beijing; Nguyen, Andy; Kim, Stuart K.

    2013-01-01

    The normal aging process is associated with stereotyped changes in gene expression, but the regulators responsible for these age-dependent changes are poorly understood. Using a novel genomics approach, we identified HOX co-factor unc-62 (Homothorax) as a developmental regulator that binds proximal to age-regulated genes and modulates lifespan. Although unc-62 is expressed in diverse tissues, its functions in the intestine play a particularly important role in modulating lifespan, as intestine-specific knockdown of unc-62 by RNAi increases lifespan. An alternatively-spliced, tissue-specific isoform of unc-62 is expressed exclusively in the intestine and declines with age. Through analysis of the downstream consequences of unc-62 knockdown, we identify multiple effects linked to aging. First, unc-62 RNAi decreases the expression of yolk proteins (vitellogenins) that aggregate in the body cavity in old age. Second, unc-62 RNAi results in a broad increase in expression of intestinal genes that typically decrease expression with age, suggesting that unc-62 activity balances intestinal resource allocation between yolk protein expression and fertility on the one hand and somatic functions on the other. Finally, in old age, the intestine shows increased expression of several aberrant genes; these UNC-62 targets are expressed predominantly in neuronal cells in developing animals, but surprisingly show increased expression in the intestine of old animals. Intestinal expression of some of these genes during aging is detrimental for longevity; notably, increased expression of insulin ins-7 limits lifespan by repressing activity of insulin pathway response factor DAF-16/FOXO in aged animals. These results illustrate how unc-62 regulation of intestinal gene expression is responsible for limiting lifespan during the normal aging process. PMID:23468654

  2. Maternal Care Determinant of Longevity?

    PubMed

    Giorgio, Marco; Renzi, Chiara; Oliveri, Serena; Pravettoni, Gabriella

    2016-04-01

    Maternal care is an essential early environment in mammals that ensures emotional regulation and adaptive fitness of progeny. Longevity and healthy aging are associated with favorable environmental factors including fitting social and behavioral features. In the present review, we discuss the findings that link rearing conditions and early maternal care with life span and aging from an evolutionary, psychological, and molecular perspective. The quality of maternal care may influence internal adaptation through a variety of parallel mechanisms including emotional regulation, stress sensitivity, coping and other behavioral strategies in response to events requiring adaptation. From a biological perspective, it regulates physiological pathways that may persist in adulthood through epigenetic mechanisms, influencing disease susceptibility and, potentially, longevity. Abnormal maternal care induces maladaptation that persists over the life span, may accelerate the onset of aging associated diseases, and shorten life span. This may have important implications in the development of preventive approaches and early interventions. PMID:27548096

  3. p66Shc longevity protein regulates the proliferation of human ovarian cancer cells.

    PubMed

    Muniyan, Sakthivel; Chou, Yu-Wei; Tsai, Te-Jung; Thomes, Paul; Veeramani, Suresh; Benigno, Benedict B; Walker, L DeEtte; McDonald, John F; Khan, Shafiq A; Lin, Fen-Fen; Lele, Subodh M; Lin, Ming-Fong

    2015-08-01

    p66Shc functions as a longevity protein in murine and exhibits oxidase activity in regulating diverse biological activities. In this study, we investigated the role of p66Shc protein in regulating ovarian cancer (OCa) cell proliferation. Among three cell lines examined, the slowest growing OVCAR-3 cells have the lowest level of p66Shc protein. Transient transfection with p66Shc cDNA expression vector in OVCAR-3 cells increases cell proliferation. Conversely, knock-down of p66Shc by shRNA in rapidly growing SKOV-3 cells results in decreased cell growth. In estrogen (E2)-treated CaOV-3 cells, elevated p66Shc protein level correlates with ROS level, ErbB-2 and ERK/MAPK activation, and cell proliferation. Further, the E2-stimulated proliferation of CaOV-3 cells was blocked by antioxidants and ErbB-2 inhibitor. Additionally, in E2-stimulated cells, the tartrate-sensitive, but not the tartrate-resistant, phosphatase activity decreases; concurrently, the tyrosine phosphorylation of ErbB-2 increases. Conversely, inhibition of phosphatase activity by L(+)-tartrate treatment increases p66Shc protein level, ErbB-2 tyrosine phosphorylation, ERK/MAPK activation, and cell growth. Further, inhibition of the ERK/MAPK pathway by PD98059 blocks E2-induced ERK/MAPK activation and cell proliferation in CaOV-3 cells. Moreover, immunohistochemical analyses showed that the p66Shc protein level was significantly higher in cancerous cells than in noncancerous cells in archival OCa tissues (n = 76; P = 0.00037). These data collectively indicate that p66Shc protein plays a critical role in up-regulating OCa progression. PMID:24395385

  4. Psychological Consequences of Longevity: The Increasing Importance of Self-Regulation in Old Age

    ERIC Educational Resources Information Center

    Freund, Alexandra M.; Nikitin, Jana; Ritter, Johannes O.

    2009-01-01

    How do changes in life expectancy and longevity affect life-span development? This paper argues that historical increases in life expectancy primarily have an impact on the later and less on the earlier parts of the life span. Increased life expectancy is both a challenge and an opportunity for positive development. A perspective is outlined…

  5. Adult longevity of certain mosquito species after larval and pupal exposure to sublethal concentration of an insect growth regulator, hexaflumuron.

    PubMed

    Vasuki, V

    1992-03-01

    Longevity of the adults of three vector species, Culex quinquefasciatus, Anopheles stephensi, and Aedes aegypti was drastically reduced when they were exposed at larval and pupal stages to sublethal concentrations of an insect growth regulator hexaflumuron. When the three species were exposed to 0.05 mg/l at the pupal stage, males and females of Cx. quinquefasciatus suffered a more shortened life span than other species. Among the females whose feeding activity was adversely affected by IGR treatment at the pupal stage, Ae. aegypti showed the minimum survival duration with LT50 of 2.74 days. PMID:1523463

  6. Genetics of aging, health, and survival: dynamic regulation of human longevity related traits

    PubMed Central

    Yashin, Anatoliy I.; Wu, Deqing; Arbeeva, Liubov S.; Arbeev, Konstantin G.; Kulminski, Alexander M.; Akushevich, Igor; Kovtun, Mikhail; Culminskaya, Irina; Stallard, Eric; Li, Miaozhu; Ukraintseva, Svetlana V.

    2015-01-01

    Background: The roles of genetic factors in human longevity would be better understood if one can use more efficient methods in genetic analyses and investigate pleiotropic effects of genetic variants on aging and health related traits. Data and methods: We used EMMAX software with modified correction for population stratification to perform genome wide association studies (GWAS) of female lifespan from the original FHS cohort. The male data from the original FHS cohort and male and female data combined from the offspring FHS cohort were used to confirm findings. We evaluated pleiotropic effects of selected genetic variants as well as gene-smoking interactions on health and aging related traits. Then we reviewed current knowledge on functional properties of genes related to detected variants. Results: The eight SNPs with genome-wide significant variants were negatively associated with lifespan in both males and females. After additional QC, two of these variants were selected for further analyses of their associations with major diseases (cancer and CHD) and physiological aging changes. Gene-smoking interactions contributed to these effects. Genes closest to detected variants appear to be involved in similar biological processes and health disorders, as those found in other studies of aging and longevity e.g., in cancer and neurodegeneration. Conclusions: The impact of genes on longevity may involve trade-off-like effects on different health traits. Genes that influence lifespan represent various molecular functions but may be involved in similar biological processes and health disorders, which could contribute to genetic heterogeneity of longevity and the lack of replication in genetic association studies. PMID:25918517

  7. The Role of Mammalian Sirtuins in the Regulation of Metabolism, Aging, and Longevity

    PubMed Central

    Satoh, Akiko; Stein, Liana

    2013-01-01

    Ever since the discovery of sirtuins a decade ago, interest in this family of NAD-dependent deacetylases has exploded, generating multiple lines of evidence implicating sirtuins as evolutionarily conserved regulators of lifespan. In mammals, it has been established that sirtuins regulate physiological responses to metabolism and stress, two key factors that affect the process of aging. Further investigation into the intimate connection among sirtuins, metabolism, and aging has implicated the activation of SIRT1 as both preventative and therapeutic measures against multiple age-associated disorders including type 2 diabetes and Alzheimer’s disease. SIRT1 activation has clear potential to not only prevent age-associated diseases but also to extend healthspan and perhaps lifespan. Sirtuin activating compounds and NAD intermediates are two promising ways to achieve these elusive goals. PMID:21879449

  8. Testing the oxidative stress hypothesis of aging in primate fibroblasts: is there a correlation between species longevity and cellular ROS production?

    PubMed

    Csiszar, Anna; Podlutsky, Andrej; Podlutskaya, Natalia; Sonntag, William E; Merlin, Steven Z; Philipp, Eva E R; Doyle, Kristian; Davila, Antonio; Recchia, Fabio A; Ballabh, Praveen; Pinto, John T; Ungvari, Zoltan

    2012-08-01

    The present study was conducted to test predictions of the oxidative stress theory of aging assessing reactive oxygen species production and oxidative stress resistance in cultured fibroblasts from 13 primate species ranging in body size from 0.25 to 120 kg and in longevity from 20 to 90 years. We assessed both basal and stress-induced reactive oxygen species production in fibroblasts from five great apes (human, chimpanzee, bonobo, gorilla, and orangutan), four Old World monkeys (baboon, rhesus and crested black macaques, and patas monkey), three New World monkeys (common marmoset, red-bellied tamarin, and woolly monkey), and one lemur (ring-tailed lemur). Measurements of cellular MitoSox fluorescence, an indicator of mitochondrial superoxide (O2(·-)) generation, showed an inverse correlation between longevity and steady state or metabolic stress-induced mitochondrial O2(·-) production, but this correlation was lost when the effects of body mass were removed, and the data were analyzed using phylogenetically independent contrasts. Fibroblasts from longer-lived primate species also exhibited superior resistance to H(2)O(2)-induced apoptotic cell death than cells from shorter-living primates. After correction for body mass and lack of phylogenetic independence, this correlation, although still discernible, fell short of significance by regression analysis. Thus, increased longevity in this sample of primates is not causally associated with low cellular reactive oxygen species generation, but further studies are warranted to test the association between increased cellular resistance to oxidative stressor and primate longevity. PMID:22219516

  9. Rosmarinus officinalis L. increases Caenorhabditis elegans stress resistance and longevity in a DAF-16, HSF-1 and SKN-1-dependent manner

    PubMed Central

    Zamberlan, D.C.; Amaral, G.P.; Arantes, L.P.; Machado, M.L.; Mizdal, C.R.; Campos, M.M.A.; Soares, F.A.A.

    2016-01-01

    Improving overall health and quality of life, preventing diseases and increasing life expectancy are key concerns in the field of public health. The search for antioxidants that can inhibit oxidative damage in cells has received a lot of attention. Rosmarinus officinalis L. represents an exceptionally rich source of bioactive compounds with pharmacological properties. In the present study, we explored the effects of the ethanolic extract of R. officinalis (eeRo) on stress resistance and longevity using the non-parasitic nematode Caenorhabditis elegans as a model. We report for the first time that eeRo increased resistance against oxidative and thermal stress and extended C. elegans longevity in an insulin/IGF signaling pathway-dependent manner. These data emphasize the eeRo beneficial effects on C. elegans under stress. PMID:27533765

  10. Dietary adenine controls adult lifespan via adenosine nucleotide biosynthesis and AMPK, and regulates the longevity benefit of caloric restriction

    PubMed Central

    Stenesen, Drew; Suh, Jae Myoung; Seo, Jin; Yu, Kweon; Lee, Kyu-Sun; Kim, Jong-Seok; Min, Kyung-Jin; Graff, Jonathan M.

    2012-01-01

    SUMMARY A common thread among conserved lifespan regulators lies within intertwined roles in metabolism and energy homeostasis. We show that heterozygous mutations of adenosine monophosphate (AMP) biosynthetic enzymes extend Drosophila lifespan. The lifespan benefit of these mutations depends upon increased AMP to adenosine triphosphate (ATP) and adenosine diphosphate (ADP) to ATP ratios and adenosine monophosphate-activated protein kinase (AMPK). Transgenic expression of AMPK in adult fat body or adult muscle, key metabolic tissues, extended lifespan, while AMPK RNAi reduced lifespan. Supplementing adenine, a substrate for AMP biosynthesis, to the diet of long-lived AMP biosynthesis mutants reversed lifespan extension. Remarkably, this simple change in diet also blocked the pro-longevity effects of dietary restriction. These data establish AMP biosynthesis, adenosine nucleotide ratios, and AMPK as determinants of adult lifespan, provide a mechanistic link between cellular anabolism and energy sensing pathways, and indicate that dietary adenine manipulations might alter metabolism to influence animal lifespan. PMID:23312286

  11. Prenatal Maternal Stress Programs Infant Stress Regulation

    ERIC Educational Resources Information Center

    Davis, Elysia Poggi; Glynn, Laura M.; Waffarn, Feizal; Sandman, Curt A.

    2011-01-01

    Objective: Prenatal exposure to inappropriate levels of glucocorticoids (GCs) and maternal stress are putative mechanisms for the fetal programming of later health outcomes. The current investigation examined the influence of prenatal maternal cortisol and maternal psychosocial stress on infant physiological and behavioral responses to stress.…

  12. The Role of Oxidative Stress in the Longevity and Insecticide Resistance Phenotype of the Major Malaria Vectors Anopheles arabiensis and Anopheles funestus.

    PubMed

    Oliver, Shüné V; Brooke, Basil D

    2016-01-01

    Oxidative stress plays numerous biological roles, both functional and pathological. The role of oxidative stress in various epidemiologically relevant biological traits in Anopheles mosquitoes is not well established. In this study, the effects of oxidative stress on the longevity and insecticide resistance phenotype in the major malaria vector species An. arabiensis and An. funestus were examined. Responses to dietary copper sulphate and hydrogen peroxide were used as proxies for the oxidative stress phenotype by determining the effect of copper on longevity and hydrogen peroxide lethal dose. Glutathione peroxidase and catalase activities were determined colorimetrically. Oxidative burden was quantified as protein carbonyl content. Changes in insecticide resistance phenotype were monitored by WHO bioassay. Insecticide resistant individuals showed an increased capacity for coping with oxidative stress, mediated by increased glutathione peroxidase and catalase activity. This effect was observed in both species, as well as in laboratory strains and F1 individuals derived from wild-caught An. funestus mothers. Phenotypic capacity for coping with oxidative stress was greatest in strains with elevated Cytochrome P450 activity. Synergism of oxidative stress defence enzymes by dietary supplementation with haematin, 3-Amino-1, 2, 4-triazole and Sodium diethyldithiocarbamate significantly increased pyrethroid-induced mortality in An. arabiensis and An. funestus. It is therefore concluded that defence against oxidative stress underlies the augmentation of the insecticide resistance phenotype associated with multiple blood-feeding. This is because multiple blood-feeding ultimately leads to a reduction of oxidative stress in insecticide resistant females, and also reduces the oxidative burden induced by DDT and pyrethroids, by inducing increased glutathione peroxidase activity. This study highlights the importance of oxidative stress in the longevity and insecticide resistance

  13. The Role of Oxidative Stress in the Longevity and Insecticide Resistance Phenotype of the Major Malaria Vectors Anopheles arabiensis and Anopheles funestus

    PubMed Central

    Oliver, Shüné V.; Brooke, Basil D.

    2016-01-01

    Oxidative stress plays numerous biological roles, both functional and pathological. The role of oxidative stress in various epidemiologically relevant biological traits in Anopheles mosquitoes is not well established. In this study, the effects of oxidative stress on the longevity and insecticide resistance phenotype in the major malaria vector species An. arabiensis and An. funestus were examined. Responses to dietary copper sulphate and hydrogen peroxide were used as proxies for the oxidative stress phenotype by determining the effect of copper on longevity and hydrogen peroxide lethal dose. Glutathione peroxidase and catalase activities were determined colorimetrically. Oxidative burden was quantified as protein carbonyl content. Changes in insecticide resistance phenotype were monitored by WHO bioassay. Insecticide resistant individuals showed an increased capacity for coping with oxidative stress, mediated by increased glutathione peroxidase and catalase activity. This effect was observed in both species, as well as in laboratory strains and F1 individuals derived from wild-caught An. funestus mothers. Phenotypic capacity for coping with oxidative stress was greatest in strains with elevated Cytochrome P450 activity. Synergism of oxidative stress defence enzymes by dietary supplementation with haematin, 3-Amino-1, 2, 4-triazole and Sodium diethyldithiocarbamate significantly increased pyrethroid-induced mortality in An. arabiensis and An. funestus. It is therefore concluded that defence against oxidative stress underlies the augmentation of the insecticide resistance phenotype associated with multiple blood-feeding. This is because multiple blood-feeding ultimately leads to a reduction of oxidative stress in insecticide resistant females, and also reduces the oxidative burden induced by DDT and pyrethroids, by inducing increased glutathione peroxidase activity. This study highlights the importance of oxidative stress in the longevity and insecticide resistance

  14. A Genome-Wide Scan Reveals Important Roles of DNA Methylation in Human Longevity by Regulating Age-Related Disease Genes

    PubMed Central

    Li, Qi-Gang; Wu, Huan; Luo, Long-Hai; Kong, Qing-Peng

    2015-01-01

    It is recognized that genetic factors contribute to human longevity. Besides the hypothesis of existence of longevity genes, another suggests that a lower frequency of risk alleles decreases the incidence of age-related diseases in the long-lived people. However, the latter finds no support from recent genetic studies. Considering the crucial role of epigenetic modification in gene regulation, we then hypothesize that suppressing disease-related genes in longevity individuals is likely achieved by epigenetic modification, e.g. DNA methylation. To test this hypothesis, we investigated the genome-wide methylation profile in 4 Chinese female centenarians and 4 middle-aged controls using methyl-DNA immunoprecipitation sequencing. 626 differentially methylated regions (DMRs) were observed between both groups. Interestingly, genes with these DMRs were enriched in age-related diseases, including type-2 diabetes, cardiovascular disease, stroke and Alzheimer’s disease. This pattern remains rather stable after including methylomes of two white individuals. Further analyses suggest that the observed DMRs likely have functional roles in regulating disease-associated gene expressions, with some genes [e.g. caspase 3 (CASP3)] being down-regulated whereas the others [i.e. interleukin 1 receptor, type 2 (IL1R2)] up-regulated. Therefore, our study suggests that suppressing the disease-related genes via epigenetic modification is an important contributor to human longevity. PMID:25793257

  15. Testing the Oxidative Stress Hypothesis of Aging in Primate Fibroblasts: Is There a Correlation Between Species Longevity and Cellular ROS Production?

    PubMed Central

    Csiszar, Anna; Podlutsky, Andrej; Podlutskaya, Natalia; Sonntag, William E.; Merlin, Steven Z.; Philipp, Eva E. R.; Doyle, Kristian; Davila, Antonio; Recchia, Fabio A.; Ballabh, Praveen; Pinto, John T.

    2012-01-01

    The present study was conducted to test predictions of the oxidative stress theory of aging assessing reactive oxygen species production and oxidative stress resistance in cultured fibroblasts from 13 primate species ranging in body size from 0.25 to 120 kg and in longevity from 20 to 90 years. We assessed both basal and stress-induced reactive oxygen species production in fibroblasts from five great apes (human, chimpanzee, bonobo, gorilla, and orangutan), four Old World monkeys (baboon, rhesus and crested black macaques, and patas monkey), three New World monkeys (common marmoset, red-bellied tamarin, and woolly monkey), and one lemur (ring-tailed lemur). Measurements of cellular MitoSox fluorescence, an indicator of mitochondrial superoxide (O2·−) generation, showed an inverse correlation between longevity and steady state or metabolic stress–induced mitochondrial O2·− production, but this correlation was lost when the effects of body mass were removed, and the data were analyzed using phylogenetically independent contrasts. Fibroblasts from longer-lived primate species also exhibited superior resistance to H2O2-induced apoptotic cell death than cells from shorter-living primates. After correction for body mass and lack of phylogenetic independence, this correlation, although still discernible, fell short of significance by regression analysis. Thus, increased longevity in this sample of primates is not causally associated with low cellular reactive oxygen species generation, but further studies are warranted to test the association between increased cellular resistance to oxidative stressor and primate longevity. PMID:22219516

  16. Cognitive emotion regulation fails the stress test

    PubMed Central

    Raio, Candace M.; Orederu, Temidayo A.; Palazzolo, Laura; Shurick, Ashley A.; Phelps, Elizabeth A.

    2013-01-01

    Cognitive emotion regulation has been widely shown in the laboratory to be an effective way to alter the nature of emotional responses. Despite its success in experimental contexts, however, we often fail to use these strategies in everyday life where stress is pervasive. The successful execution of cognitive regulation relies on intact executive functioning and engagement of the prefrontal cortex, both of which are rapidly impaired by the deleterious effects of stress. Because it is specifically under stressful conditions that we may benefit most from such deliberate forms of emotion regulation, we tested the efficacy of cognitive regulation after stress exposure. Participants first underwent fear-conditioning, where they learned that one stimulus (CS+) predicted an aversive outcome but another predicted a neutral outcome (CS−). Cognitive regulation training directly followed where participants were taught to regulate fear responses to the aversive stimulus. The next day, participants underwent an acute stress induction or a control task before repeating the fear-conditioning task using these newly acquired regulation skills. Skin conductance served as an index of fear arousal, and salivary α-amylase and cortisol concentrations were assayed as neuroendocrine markers of stress response. Although groups showed no differences in fear arousal during initial fear learning, nonstressed participants demonstrated robust fear reduction following regulation training, whereas stressed participants showed no such reduction. Our results suggest that stress markedly impairs the cognitive regulation of emotion and highlights critical limitations of this technique to control affective responses under stress. PMID:23980142

  17. Peroxiredoxin 5 confers protection against oxidative stress and apoptosis and also promotes longevity in Drosophila.

    PubMed

    Radyuk, Svetlana N; Michalak, Katarzyna; Klichko, Vladimir I; Benes, Judith; Rebrin, Igor; Sohal, Rajindar S; Orr, William C

    2009-04-15

    Peroxiredoxin 5 is a distinct isoform of the peroxiredoxin gene family. The antioxidative and anti-apoptotic functions of peroxiredoxin 5 have been extensively demonstrated in cell culture experiments. In the present paper, we provide the first functional analysis of peroxiredoxin 5 in a multicellular organism, Drosophila melanogaster. Similar to its mammalian, yeast or human counterparts, dPrx5 (Drosophila peroxiredoxin 5) is expressed in several cellular compartments, including the cytosol, nucleus and the mitochondrion. Global overexpression of dPrx5 in flies increased resistance to oxidative stress and extended their life span by up to 30% under normal conditions. The dprx5(-/-) null flies were comparatively more susceptible to oxidative stress, had higher incidence of apoptosis, and a shortened life span. TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling) analysis revealed that the dprx5(-/-) null mutant had discernible tissue-specific apoptotic patterns, similar to those observed in control flies exposed to paraquat. In addition, apoptosis was particularly notable in oenocytes. During development the dPrx5 levels co-varied with ecdysone pulses, suggesting inter-relationship between ecdystreroids and dPrx5 expression. The importance of dPrx5 for development was further underscored by the embryonic lethal phenotype of progeny derived from the dprx5(-/-) null mutant. Results from the present study suggest that the antioxidant and anti-apoptotic activities of dPrx5 play a critical role in development and aging of the fly. PMID:19128239

  18. Resistance to Genotoxic Stresses in Arctica islandica, the Longest Living Noncolonial Animal: Is Extreme Longevity Associated With a Multistress Resistance Phenotype?

    PubMed Central

    Ungvari, Zoltan; Sosnowska, Danuta; Mason, Jeffrey B.; Gruber, Heike

    2013-01-01

    Bivalve molluscs are newly discovered models of successful aging. Here, we test the hypothesis that extremely long-lived bivalves are not uniquely resistant to oxidative stressors (eg, tert-butyl hydroperoxide, as demonstrated in previous studies) but exhibit a multistress resistance phenotype. We contrasted resistance (in terms of organismal mortality) to genotoxic stresses (including topoisomerase inhibitors, agents that cross-link DNA or impair genomic integrity through DNA alkylation or methylation) and to mitochondrial oxidative stressors in three bivalve mollusc species with dramatically differing life spans: Arctica islandica (ocean quahog), Mercenaria mercenaria (northern quahog), and the Atlantic bay scallop, Argopecten irradians irradians (maximum species life spans: >500, >100, and ~2 years, respectively). With all stressors, the short-lived A i irradians were significantly less resistant than the two longer lived species. Arctica islandica were consistently more resistant than M mercenaria to mortality induced by oxidative stressors as well as DNA methylating agent nitrogen mustard and the DNA alkylating agent methyl methanesulfonate. The same trend was not observed for genotoxic agents that act through cross-linking DNA. In contrast, M mercenaria tended to be more resistant to epirubicin and genotoxic stressors, which cause DNA damage by inhibiting topoisomerases. To our knowledge, this is the first study comparing resistance to genotoxic stressors in bivalve mollusc species with disparate longevities. In line with previous studies of comparative stress resistance and longevity, our data extends, at least in part, the evidence for the hypothesis that an association exists between longevity and a general resistance to multiplex stressors, not solely oxidative stress. This work also provides justification for further investigation into the interspecies differences in stress response signatures induced by a diverse array of stressors in short-lived and

  19. Longevity overfishing

    NASA Astrophysics Data System (ADS)

    Beamish, R. J.; McFarlane, G. A.; Benson, A.

    2006-02-01

    Overfishing is generally considered to be a reduction in biomass below some critical level such that the remaining fish are not able to replenish the population. We propose that the removal of large numbers of older age groups by fishing is also a form of overfishing, which we identify as longevity overfishing. Longevity overfishing is a potentially important consideration for the commercial fisheries off Canada’s Pacific coast that are dominated by species that have maximum ages of 30 years or longer. Sablefish is one of the key long-lived species that is managed for biomass and not longevity. An age structured model showed that if younger fish do not have the same productivity per unit biomass as older fish, the population depleted of older fishes would not recover after a shift of carrying capacity from a prolonged period of poor productivity to a more productive ocean ecosystem. Current management of long-lived species implicitly assumes that young fish will have the same productivity as older fishes, an assumption that is not supported by a sparse literature, and is thus not precautionary. We propose that the evolved age structure is an indication that long-lived species must be managed for longevity as well as biomass, which requires a management time frame that is decades and not annual.

  20. GROWTH REGULATING FACTOR5 Stimulates Arabidopsis Chloroplast Division, Photosynthesis, and Leaf Longevity1[OPEN

    PubMed Central

    Vercruyssen, Liesbeth; Tognetti, Vanesa B.; Gonzalez, Nathalie; Van Dingenen, Judith; De Milde, Liesbeth; Bielach, Agnieszka; De Rycke, Riet; Van Breusegem, Frank; Inzé, Dirk

    2015-01-01

    Arabidopsis (Arabidopsis thaliana) leaf development relies on subsequent phases of cell proliferation and cell expansion. During the proliferation phase, chloroplasts need to divide extensively, and during the transition from cell proliferation to expansion, they differentiate into photosynthetically active chloroplasts, providing the plant with energy. The transcription factor GROWTH REGULATING FACTOR5 (GRF5) promotes the duration of the cell proliferation period during leaf development. Here, it is shown that GRF5 also stimulates chloroplast division, resulting in a higher chloroplast number per cell with a concomitant increase in chlorophyll levels in 35S:GRF5 leaves, which can sustain higher rates of photosynthesis. Moreover, 35S:GRF5 plants show delayed leaf senescence and are more tolerant for growth on nitrogen-depleted medium. Cytokinins also stimulate leaf growth in part by extending the cell proliferation phase, simultaneously delaying the onset of the cell expansion phase. In addition, cytokinins are known to be involved in chloroplast development, nitrogen signaling, and senescence. Evidence is provided that GRF5 and cytokinins synergistically enhance cell division and chlorophyll retention after dark-induced senescence, which suggests that they also cooperate to stimulate chloroplast division and nitrogen assimilation. Taken together with the increased leaf size, ectopic expression of GRF5 has great potential to improve plant productivity. PMID:25604530

  1. Reduced Expression of MYC Increases Longevity and Enhances Healthspan

    PubMed Central

    Hofmann, Jeffrey W.; Zhao, Xiaoai; De Cecco, Marco; Peterson, Abigail L.; Pagliaroli, Luca; Manivannan, Jayameenakshi; Hubbard, Gene B.; Ikeno, Yuji; Zhang, Yongqing; Feng, Bin; Li, Xiaxi; Serre, Thomas; Qi, Wenbo; Van Remmen, Holly; Miller, Richard A.; Bath, Kevin G.; de Cabo, Rafael; Xu, Haiyan; Neretti, Nicola; Sedivy, John M.

    2015-01-01

    SUMMARY MYC is a highly pleiotropic transcription factor whose deregulation promotes cancer. In contrast, we find that Myc haploinsufficient (Myc+/−) mice exhibit increased lifespan. They show resistance to several age-associated pathologies, including osteoporosis, cardiac fibrosis and immunosenescence. They also appear to be more active, with a higher metabolic rate and healthier lipid metabolism. Transcriptomic analysis reveals a gene expression signature enriched for metabolic and immune processes. The ancestral role of MYC as a regulator of ribosome biogenesis is reflected in reduced protein translation, which is inversely correlated with longevity. We also observe changes in nutrient and energy sensing pathways, including reduced serum IGF-1, increased AMPK activity, and decreased AKT, TOR and S6K activities. In contrast to observations in other longevity models, Myc+/− mice do not show improvements in stress management pathways. Our findings indicate that MYC activity has a significant impact on longevity and multiple aspects of mammalian healthspan. PMID:25619689

  2. Reduced expression of MYC increases longevity and enhances healthspan.

    PubMed

    Hofmann, Jeffrey W; Zhao, Xiaoai; De Cecco, Marco; Peterson, Abigail L; Pagliaroli, Luca; Manivannan, Jayameenakshi; Hubbard, Gene B; Ikeno, Yuji; Zhang, Yongqing; Feng, Bin; Li, Xiaxi; Serre, Thomas; Qi, Wenbo; Van Remmen, Holly; Miller, Richard A; Bath, Kevin G; de Cabo, Rafael; Xu, Haiyan; Neretti, Nicola; Sedivy, John M

    2015-01-29

    MYC is a highly pleiotropic transcription factor whose deregulation promotes cancer. In contrast, we find that Myc haploinsufficient (Myc(+/-)) mice exhibit increased lifespan. They show resistance to several age-associated pathologies, including osteoporosis, cardiac fibrosis, and immunosenescence. They also appear to be more active, with a higher metabolic rate and healthier lipid metabolism. Transcriptomic analysis reveals a gene expression signature enriched for metabolic and immune processes. The ancestral role of MYC as a regulator of ribosome biogenesis is reflected in reduced protein translation, which is inversely correlated with longevity. We also observe changes in nutrient and energy sensing pathways, including reduced serum IGF-1, increased AMPK activity, and decreased AKT, TOR, and S6K activities. In contrast to observations in other longevity models, Myc(+/-) mice do not show improvements in stress management pathways. Our findings indicate that MYC activity has a significant impact on longevity and multiple aspects of mammalian healthspan. PMID:25619689

  3. Mitotic degradation of yeast Fkh1 by the Anaphase Promoting Complex is required for normal longevity, genomic stability and stress resistance

    PubMed Central

    Malo, Mackenzie E.; Postnikoff, Spike D.L.; Arnason, Terra G.; Harkness, Troy A.A.

    2016-01-01

    The Saccharomyces cerevisiae Forkhead Box (Fox) orthologs, Forkheads (Fkh) 1 and 2, are conserved transcription factors required for stress response, cell cycle progression and longevity. These yeast proteins play a key role in mitotic progression through activation of the ubiquitin E3 ligase Anaphase Promoting Complex (APC) via transcriptional control. Here, we used genetic and molecular analyses to demonstrate that the APC E3 activity is necessary for mitotic Fkh1 protein degradation and subsequent cell cycle progression. We report that Fkh1 protein degradation occurs specifically during mitosis, requires APCCdc20 and proteasome activity, and that a stable Fkh1 mutant reduces normal chronological lifespan, increases genomic instability, and increases sensitivity to stress. Our data supports a model whereby cell cycle progression through mitosis and G1 requires the targeted degradation of Fkh1 by the APC. This is significant to many fields as these results impact our understanding of the mechanisms underpinning the control of aging and cancer. PMID:27099939

  4. Common mechanisms for calorie restriction and adenylyl cyclase type 5 knockout models of longevity.

    PubMed

    Yan, Lin; Park, Ji Yeon; Dillinger, Jean-Guillaume; De Lorenzo, Mariana S; Yuan, Chujun; Lai, Lo; Wang, Chunbo; Ho, David; Tian, Bin; Stanley, William C; Auwerx, Johan; Vatner, Dorothy E; Vatner, Stephen F

    2012-12-01

    Adenylyl cyclase type 5 knockout mice (AC5 KO) live longer and are stress resistant, similar to calorie restriction (CR). AC5 KO mice eat more, but actually weigh less and accumulate less fat compared with WT mice. CR applied to AC5 KO results in rapid decrease in body weight, metabolic deterioration, and death. These data suggest that despite restricted food intake in CR, but augmented food intake in AC5 KO, the two models affect longevity and metabolism similarly. To determine shared molecular mechanisms, mRNA expression was examined genome-wide for brain, heart, skeletal muscle, and liver. Significantly more genes were regulated commonly rather than oppositely in all the tissues in both models, indicating commonality between AC5 KO and CR. Gene ontology analysis identified many significantly regulated, tissue-specific pathways shared by the two models, including sensory perception in heart and brain, muscle function in skeletal muscle, and lipid metabolism in liver. Moreover, when comparing gene expression changes in the heart under stress, the glutathione regulatory pathway was consistently upregulated in the longevity models but downregulated with stress. In addition, AC5 and CR shared changes in genes and proteins involved in the regulation of longevity and stress resistance, including Sirt1, ApoD, and olfactory receptors in both young- and intermediate-age mice. Thus, the similarly regulated genes and pathways in AC5 KO and CR mice, particularly related to the metabolic phenotype, suggest a unified theory for longevity and stress resistance. PMID:23020244

  5. Regulation of Synaptic nlg-1/Neuroligin Abundance by the skn-1/Nrf Stress Response Pathway Protects against Oxidative Stress

    PubMed Central

    Staab, Trisha A.; Egrafov, Oleg; Knowles, James A.; Sieburth, Derek

    2014-01-01

    The Nrf family of transcription factors mediates adaptive responses to stress and longevity, but the identities of the crucial Nrf targets, and the tissues in which they function in multicellular organisms to promote survival, are not known. Here, we use whole transcriptome RNA sequencing to identify 810 genes whose expression is controlled by the SKN-1/Nrf2 negative regulator WDR-23 in the nervous system of Caenorhabditis elegans. Among the genes identified is the synaptic cell adhesion molecule nlg-1/neuroligin. We find that the synaptic abundance of NLG-1 protein increases following pharmacological treatments that generate oxidative stress or by the genetic activation of skn-1. Increasing nlg-1 dosage correlates with increased survival in response to oxidative stress, whereas genetic inactivation of nlg-1 reduces survival and impairs skn-1-mediated stress resistance. We identify a canonical SKN-1 binding site in the nlg-1 promoter that binds to SKN-1 in vitro and is necessary for SKN-1 and toxin-mediated increases in nlg-1 expression in vivo. Together, our results suggest that SKN-1 activation in the nervous system can confer protection to organisms in response to stress by directly regulating nlg-1/neuroligin expression. PMID:24453991

  6. SIRT1 associates with eIF2-alpha and regulates the cellular stress response

    PubMed Central

    Ghosh, Hiyaa Singhee; Reizis, Boris; Robbins, Paul D.

    2011-01-01

    SIRT1 is a NAD+ dependent protein deacetylase known to increase longevity in model organisms. SIRT1 regulates cellular response to oxidative and/or genotoxic stress by regulating proteins such as p53 and FOXO. The eukaryotic initiation factor-2, eIF2, plays a critical role in the integrated stress response pathway. Under cellular stress, phosphorylation of the alpha subunit of eIF2 is essential for immediate shut-off of translation and activation of stress response genes. Here we demonstrate that SIRT1 interacts with eIF2α. Loss of SIRT1 results in increased phosphorylation of eIF2α. However, the downstream stress induced signaling pathway is compromised in SIRT1-deficient cells, indicated by delayed expression of the downstream target genes CHOP and GADD34 and a slower post-stress translation recovery. Finally, SIRT1 co-immunoprecipitates with mediators of eIF2α dephosphorylation, GADD34 and CreP, suggesting a role for SIRT1 in the negative feedback regulation of eIF2α phosphorylation. PMID:22355666

  7. Regulated cell death and adaptive stress responses.

    PubMed

    Galluzzi, Lorenzo; Bravo-San Pedro, José Manuel; Kepp, Oliver; Kroemer, Guido

    2016-06-01

    Eukaryotic cells react to potentially dangerous perturbations of the intracellular or extracellular microenvironment by activating rapid (transcription-independent) mechanisms that attempt to restore homeostasis. If such perturbations persist, cells may still try to cope with stress by activating delayed and robust (transcription-dependent) adaptive systems, or they may actively engage in cellular suicide. This regulated form of cell death can manifest with various morphological, biochemical and immunological correlates, and constitutes an ultimate attempt of stressed cells to maintain organismal homeostasis. Here, we dissect the general organization of adaptive cellular responses to stress, their intimate connection with regulated cell death, and how the latter operates for the preservation of organismal homeostasis. PMID:27048813

  8. Inhibition of p66ShcA Longevity Gene Rescues Podocytes from HIV-1-induced Oxidative Stress and Apoptosis*

    PubMed Central

    Husain, Mohammad; Meggs, Leonard G.; Vashistha, Himanshu; Simoes, Sonia; Griffiths, Kevin O.; Kumar, Dileep; Mikulak, Joanna; Mathieson, Peter W.; Saleem, Moin A.; Del Valle, Luis; Pina-Oviedo, Sergio; Wang, Jin Ying; Seshan, Surya V.; Malhotra, Ashwani; Reiss, Krzysztof; Singhal, Pravin C.

    2009-01-01

    Glomerular visceral epithelial cells (podocytes) play a critical role in the pathogenesis of human immunodeficiency virus (HIV)-associated nephropathy. A key question concerns the mechanism(s) by which the HIV-1 genome alters the phenotype of the highly specialized, terminally differentiated podocytes. Here, using an in vitro system of conditionally immortalized differentiated human podocytes (CIDHPs), we document a pivotal role for the p66ShcA protein in HIV-1-induced reactive oxygen species generation and CIDHP apoptosis. CIDHP transfected with truncated HIV-1 construct (NL4-3) exhibit increased reactive oxygen species metabolism, DNA strand breaks, and a 5-fold increase in apoptosis, whereas the opposite was true for NL4-3/CIDHP co-transfected with mu-36p66ShcA (mu-36) dominant negative expression vector or isoform-specific p66-small interfering RNA. Phosphorylation at Ser-36 of the wild type p66ShcA protein, required for p66ShcA redox function and inhibition of the potent stress response regulator Foxo3a, was unchanged in mu-36/NL4-3/CIDHP but increased in NL4-3/CIDHP. Acute knockdown of Foxo3a by small interfering RNA induced a 50% increase in mu-36/NL4-3/CIDHP apoptosis, indicating that Foxo3a-dependent responses promote the survival phenotype in mu-36 cells. We conclude that inhibition of p66ShcA redox activity prevents generation of HIV-1 stress signals and activation of the CIDHP apoptosis program. PMID:19383602

  9. Metabolism, longevity and epigenetics.

    PubMed

    Cosentino, Claudia; Mostoslavsky, Raul

    2013-05-01

    Metabolic homeostasis and interventions that influence nutrient uptake are well-established means to influence lifespan even in higher eukaryotes. Until recently, the molecular mechanisms explaining such an effect remained scantily understood. Sirtuins are a group of protein deacetylases that depend on the metabolic intermediate NAD(+) as a cofactor for their function. For this reason they sense metabolic stress and in turn function at multiple levels to exert proper metabolic adaptation. Among other things, sirtuins can perform as histone deacetylases inducing epigenetic changes to modulate transcription and DNA repair. Recent studies have indicated that beyond sirtuins, the activity of other chromatin modifiers, such as histone acetyl transferases, might also be tightly linked to the availability of their intermediate metabolite acetyl-CoA. We summarize current knowledge of the emerging concepts indicating close crosstalk between the epigenetic machineries able to sense metabolic stress, their adaptive metabolic responses and their potential role in longevity. PMID:23467663

  10. Long live FOXO: unraveling the role of FOXO proteins in aging and longevity.

    PubMed

    Martins, Rute; Lithgow, Gordon J; Link, Wolfgang

    2016-04-01

    Aging constitutes the key risk factor for age-related diseases such as cancer and cardiovascular and neurodegenerative disorders. Human longevity and healthy aging are complex phenotypes influenced by both environmental and genetic factors. The fact that genetic contribution to lifespan strongly increases with greater age provides basis for research on which "protective genes" are carried by long-lived individuals. Studies have consistently revealed FOXO (Forkhead box O) transcription factors as important determinants in aging and longevity. FOXO proteins represent a subfamily of transcription factors conserved from Caenorhabditis elegans to mammals that act as key regulators of longevity downstream of insulin and insulin-like growth factor signaling. Invertebrate genomes have one FOXO gene, while mammals have four FOXO genes: FOXO1, FOXO3, FOXO4, and FOXO6. In mammals, this subfamily is involved in a wide range of crucial cellular processes regulating stress resistance, metabolism, cell cycle arrest, and apoptosis. Their role in longevity determination is complex and remains to be fully elucidated. Throughout this review, the mechanisms by which FOXO factors contribute to longevity will be discussed in diverse animal models, from Hydra to mammals. Moreover, compelling evidence of FOXOs as contributors for extreme longevity and health span in humans will be addressed. PMID:26643314

  11. Exploring the Role of Genetic Variability and Lifestyle in Oxidative Stress Response for Healthy Aging and Longevity

    PubMed Central

    Dato, Serena; Crocco, Paolina; D’Aquila, Patrizia; de Rango, Francesco; Bellizzi, Dina; Rose, Giuseppina; Passarino, Giuseppe

    2013-01-01

    Oxidative stress is both the cause and consequence of impaired functional homeostasis characterizing human aging. The worsening efficiency of stress response with age represents a health risk and leads to the onset and accrual of major age-related diseases. In contrast, centenarians seem to have evolved conservative stress response mechanisms, probably derived from a combination of a diet rich in natural antioxidants, an active lifestyle and a favorable genetic background, particularly rich in genetic variants able to counteract the stress overload at the level of both nuclear and mitochondrial DNA. The integration of these factors could allow centenarians to maintain moderate levels of free radicals that exert beneficial signaling and modulator effects on cellular metabolism. Considering the hot debate on the efficacy of antioxidant supplementation in promoting healthy aging, in this review we gathered the existing information regarding genetic variability and lifestyle factors which potentially modulate the stress response at old age. Evidence reported here suggests that the integration of lifestyle factors (moderate physical activity and healthy nutrition) and genetic background could shift the balance in favor of the antioxidant cellular machinery by activating appropriate defense mechanisms in response to exceeding external and internal stress levels, and thus possibly achieving the prospect of living a longer life. PMID:23965963

  12. Exploring the role of genetic variability and lifestyle in oxidative stress response for healthy aging and longevity.

    PubMed

    Dato, Serena; Crocco, Paolina; D'Aquila, Patrizia; de Rango, Francesco; Bellizzi, Dina; Rose, Giuseppina; Passarino, Giuseppe

    2013-01-01

    Oxidative stress is both the cause and consequence of impaired functional homeostasis characterizing human aging. The worsening efficiency of stress response with age represents a health risk and leads to the onset and accrual of major age-related diseases. In contrast, centenarians seem to have evolved conservative stress response mechanisms, probably derived from a combination of a diet rich in natural antioxidants, an active lifestyle and a favorable genetic background, particularly rich in genetic variants able to counteract the stress overload at the level of both nuclear and mitochondrial DNA. The integration of these factors could allow centenarians to maintain moderate levels of free radicals that exert beneficial signaling and modulator effects on cellular metabolism. Considering the hot debate on the efficacy of antioxidant supplementation in promoting healthy aging, in this review we gathered the existing information regarding genetic variability and lifestyle factors which potentially modulate the stress response at old age. Evidence reported here suggests that the integration of lifestyle factors (moderate physical activity and healthy nutrition) and genetic background could shift the balance in favor of the antioxidant cellular machinery by activating appropriate defense mechanisms in response to exceeding external and internal stress levels, and thus possibly achieving the prospect of living a longer life. PMID:23965963

  13. Stress chaperone mortalin regulates human melanogenesis.

    PubMed

    Wadhwa, Renu; Priyandoko, Didik; Gao, Ran; Widodo, Nashi; Nigam, Nupur; Li, Ling; Ahn, Hyo Min; Yun, Chae-Ok; Ando, Nobuhiro; Mahe, Christian; Kaul, Sunil C

    2016-07-01

    In order to identify the cellular factors involved in human melanogenesis, we carried out shRNA-mediated loss-of-function screening in conjunction with induction of melanogenesis by 1-oleoyl-2-acetyl-glycerol (OAG) in human melanoma cells using biochemical and visual assays. Gene targets of the shRNAs (that caused loss of OAG-induced melanogenesis) and their pathways, as determined by bioinformatics, revealed involvement of proteins that regulate cell stress response, mitochondrial functions, proliferation, and apoptosis. We demonstrate, for the first time, that the mitochondrial stress chaperone mortalin is crucial for melanogenesis. Upregulation of mortalin was closely associated with melanogenesis in in vitro cell-based assays and clinical samples of keloids with hyperpigmentation. Furthermore, its knockdown resulted in compromised melanogenesis. The data proposed mortalin as an important protein that may be targeted to manipulate pigmentation for cosmetic and related disease therapeutics. PMID:27056733

  14. Longevity: epigenetic and biomolecular aspects.

    PubMed

    Taormina, Giusi; Mirisola, Mario G

    2015-04-01

    Many aging theories and their related molecular mechanisms have been proposed. Simple model organisms such as yeasts, worms, fruit flies and others have massively contributed to their clarification, and many genes and pathways have been associated with longevity regulation. Among them, insulin/IGF-1 plays a key and evolutionary conserved role. Interestingly, dietary interventions can modulate this pathway. Calorie restriction (CR), intermittent fasting, and protein and amino acid restriction prolong the lifespan of mammals by IGF-1 regulation. However, some recent findings support the hypothesis that the long-term effects of diet also involve epigenetic mechanisms. In this review, we describe the best characterized aging pathways and highlight the role of epigenetics in diet-mediated longevity. PMID:25883209

  15. Rec-8 dimorphism affects longevity, stress resistance and X-chromosome nondisjunction in C. elegans, and replicative lifespan in S. cerevisiae

    PubMed Central

    Ayyadevara, Srinivas; Tazearslan, Çagdas; Alla, Ramani; Jiang, James C.; Jazwinski, S. Michal; Shmookler Reis, Robert J.

    2014-01-01

    A quantitative trait locus (QTL) in the nematode C. elegans, “lsq4,” was recently implicated by mapping longevity genes. QTLs for lifespan and three stress-resistance traits coincided within a span of <300 kbp, later narrowed to <200 kbp. A single gene in this interval is now shown to modulate all lsq4-associated traits. Full-genome analysis of transcript levels indicates that lsq4 contains a dimorphic gene governing the expression of many sperm-specific genes, suggesting an effect on spermatogenesis. Quantitative analysis of allele-specific transcripts encoded within the lsq4 interval revealed significant, 2- to 15-fold expression differences for 10 of 33 genes. Fourteen “dual-candidate” genes, implicated by both position and expression, were tested for RNA-interference effects on QTL-linked traits. In a strain carrying the shorter-lived allele, knockdown of rec-8 (encoding a meiotic cohesin) reduced its transcripts 4-fold, to a level similar to the longer-lived strain, while extending lifespan 25–26%, whether begun before fertilization or at maturity. The short-lived lsq4 allele also conferred sensitivity to oxidative and thermal stresses, and lower male frequency (reflecting X-chromosome non-disjunction), traits reversed uniquely by rec-8 knockdown. A strain bearing the longer-lived lsq4 allele, differing from the short-lived strain at <0.3% of its genome, derived no lifespan or stress-survival benefit from rec-8 knockdown. We consider two possible explanations: high rec-8 expression may include increased “leaky” expression in mitotic cells, leading to deleterious destabilization of somatic genomes; or REC-8 may act entirely in germ-line meiotic cells to reduce aberrations such as non-disjunction, thereby blunting a stress-resistance response mediated by innate immunity. Replicative lifespan was extended 20% in haploid S. cerevisiae (BY4741) by deletion of REC8, orthologous to nematode rec-8, implying that REC8 disruption of mitotic-cell survival

  16. Specific roles of tocopherols and tocotrienols in seed longevity and germination tolerance to abiotic stress in transgenic rice.

    PubMed

    Chen, Defu; Li, Yanlan; Fang, Tao; Shi, Xiaoli; Chen, Xiwen

    2016-03-01

    Tocopherols and tocotrienols are lipophilic antioxidants that are abundant in plant seeds. Although their roles have been extensively studied, our understanding of their functions in rice seeds is still limited. In this study, on the basis of available RNAi rice plants constitutively silenced for homogentisate phytyltransferase (HPT) and tocopherol cyclase (TC), we developed transgenic plants that silenced homogentisate geranylgeranyl transferase (HGGT). All the RNAi plants showed significantly reduced germination percentages and a higher proportion of abnormal seedlings than the control plants, with HGGT transgenics showing the most severe phenotype. The accelerated aging phenotype corresponded well with the amount of H2O2 accumulated in the embryo, glucose level, and ion leakage, but not with the amount of O(2-) accumulated in the embryo and lipid hydroperoxides levels in these genotypes. Under abiotic stress conditions, HPT and TC transgenics showed lower germination percentage and seedling growth than HGGT transgenics, while HGGT transgenics showed almost the same status as the wild type. Therefore, we proposed that tocopherols in the germ may protect the embryo from reactive oxygen species under both accelerated aging and stress conditions, whereas tocotrienols in the pericarp may exclusively help in reducing the metabolic activity of the seed during accelerated aging. PMID:26810451

  17. RNA Regulation of Lipotoxicity and Metabolic Stress.

    PubMed

    Caputa, George; Schaffer, Jean E

    2016-07-01

    Noncoding RNAs are an emerging class of nonpeptide regulators of metabolism. Metabolic diseases and the altered metabolic environment induce marked changes in levels of microRNAs and long noncoding RNAs. Furthermore, recent studies indicate that a growing number of microRNAs and long noncoding RNAs serve as critical mediators of adaptive and maladaptive responses through their effects on gene expression. The metabolic environment also has a profound impact on the functions of classes of noncoding RNAs that have been thought primarily to subserve housekeeping functions in cells-ribosomal RNAs, transfer RNAs, and small nucleolar RNAs. Evidence is accumulating that these RNAs are also components of an integrated cellular response to the metabolic milieu. This Perspective discusses the different classes of noncoding RNAs and their contributions to the pathogenesis of metabolic stress. PMID:27288006

  18. Birth Month Affects Longevity

    ERIC Educational Resources Information Center

    Abel, Ernest L.; Kruger, Michael L.

    2010-01-01

    The authors examined the association between birth month and longevity for major league baseball players. Players born in the month of November had the greatest longevities whereas those born in June had the shortest life spans. These differences remained after controlling for covariates such as birth year, career length, age at debut, height, and…

  19. Exercise, Aging and Longevity.

    ERIC Educational Resources Information Center

    Brown, Stanley P.; Cundiff, David E.

    1988-01-01

    The question of whether or not a lifelong program of exercise actually has a bearing on longevity is discussed. The effects of exercise on the aging process, and the longevity-exercise relationship are reviewed. The conflicting evidence on the subject is presented. (JL)

  20. Proteomics of red and white corolla limbs in petunia reveals a novel function of the anthocyanin regulator ANTHOCYANIN1 in determining flower longevity.

    PubMed

    Prinsi, Bhakti; Negri, Alfredo S; Quattrocchio, Francesca M; Koes, Ronald E; Espen, Luca

    2016-01-10

    The Petunia hybrida ANTHOCYANIN1 (AN1) gene encodes a transcription factor that regulates both the expression of genes involved in anthocyanin synthesis and the acidification of the vacuolar lumen in corolla epidermal cells. In this work, the comparison between the red flowers of the R27 line with the white flowers of the isogenic an1 mutant line W225 showed that the AN1 gene has further pleiotropic effects on flavonoid biosynthesis as well as on distant physiological traits. The proteomic profiling showed that the an1 mutation was associated to changes in accumulation of several proteins, affecting both anthocyanin synthesis and primary metabolism. The flavonoid composition study confirmed that the an1 mutation provoked a broad attenuation of the entire flavonoid pathway, probably by indirect biochemical events. Moreover, proteomic changes and variation of biochemical parameters revealed that the an1 mutation induced a delay in the onset of flower senescence in W225, as supported by the enhanced longevity of the W225 flowers in planta and the loss of sensitivity of cut flowers to sugar. This study suggests that AN1 is possibly involved in the perception and/or transduction of ethylene signal during flower senescence. PMID:26459403

  1. Thermosensation and longevity.

    PubMed

    Xiao, Rui; Liu, Jianfeng; Xu, X Z Shawn

    2015-09-01

    Temperature has profound effects on behavior and aging in both poikilotherms and homeotherms. To thrive under the ever fluctuating environmental temperatures, animals have evolved sophisticated mechanisms to sense and adapt to temperature changes. Animals sense temperature through various molecular thermosensors, such as thermosensitive transient receptor potential (TRP) channels expressed in neurons, keratinocytes, and intestine. These evolutionarily conserved thermosensitive TRP channels feature distinct activation thresholds, thereby covering a wide spectrum of ambient temperature. Temperature changes trigger complex thermosensory behaviors. Due to the simplicity of the nervous system in model organisms such as Caenorhabditis elegans and Drosophila, the mechanisms of thermosensory behaviors in these species have been extensively studied at the circuit and molecular levels. While much is known about temperature regulation of behavior, it remains largely unclear how temperature affects aging. Recent studies in C. elegans demonstrate that temperature modulation of longevity is not simply a passive thermodynamic phenomenon as suggested by the rate-of-living theory, but rather a process that is actively regulated by genes, including those encoding thermosensitive TRP channels. In this review, we discuss our current understanding of thermosensation and its role in aging. PMID:26101089

  2. Staying Alive: Molecular Aspects of Seed Longevity.

    PubMed

    Sano, Naoto; Rajjou, Loïc; North, Helen M; Debeaujon, Isabelle; Marion-Poll, Annie; Seo, Mitsunori

    2016-04-01

    Mature seeds are an ultimate physiological status that enables plants to endure extreme conditions such as high and low temperature, freezing and desiccation. Seed longevity, the period over which seed remains viable, is an important trait not only for plant adaptation to changing environments, but also, for example, for agriculture and conservation of biodiversity. Reduction of seed longevity is often associated with oxidation of cellular macromolecules such as nucleic acids, proteins and lipids. Seeds possess two main strategies to combat these stressful conditions: protection and repair. The protective mechanism includes the formation of glassy cytoplasm to reduce cellular metabolic activities and the production of antioxidants that prevent accumulation of oxidized macromolecules during seed storage. The repair system removes damage accumulated in DNA, RNA and proteins upon seed imbibition through enzymes such as DNA glycosylase and methionine sulfoxide reductase. In addition to longevity, dormancy is also an important adaptive trait that contributes to seed lifespan. Studies in Arabidopsis have shown that the seed-specific transcription factor ABSCISIC ACID-INSENSITIVE3 (ABI3) plays a central role in ABA-mediated seed dormancy and longevity. Seed longevity largely relies on the viability of embryos. Nevertheless, characterization of mutants with altered seed coat structure and constituents has demonstrated that although the maternally derived cell layers surrounding the embryos are dead, they have a significant impact on longevity. PMID:26637538

  3. Mitochondrial-Nuclear Epistasis: Implications for Human Aging and Longevity

    PubMed Central

    Tranah, Gregory

    2010-01-01

    There is substantial evidence that mitochondria are involved in the aging process. Mitochondrial function requires the coordinated expression of hundreds of nuclear genes and a few dozen mitochondrial genes, many of which have been associated with either extended or shortened life span. Impaired mitochondrial function resulting from mtDNA and nuclear DNA variation is likely to contribute to an imbalance in cellular energy homeostasis, increased vulnerability to oxidative stress, and an increased rate of cellular senescence and aging. The complex genetic architecture of mitochondria suggests that there may be an equally complex set of gene interactions (epistases) involving genetic variation in the nuclear and mitochondrial genomes. Results from Drosophila suggest that the effects of mtDNA haplotypes on longevity vary among different nuclear allelic backgrounds, which could account for the inconsistent associations that have been observed between mitochondrial DNA (mtDNA) haplogroups and survival in humans. A diversity of pathways may influence the way mitochondria and nuclear – mitochondrial interactions modulate longevity, including: oxidative phosphorylation; mitochondrial uncoupling; antioxidant defenses; mitochondrial fission and fusion; and sirtuin regulation of mitochondrial genes. We hypothesize that aging and longevity, as complex traits having a significant genetic component, are likely to be controlled by nuclear gene variants interacting with both inherited and somatic mtDNA variability. PMID:20601194

  4. Has gene duplication impacted the evolution of Eutherian longevity?

    PubMed

    Doherty, Aoife; de Magalhães, João Pedro

    2016-10-01

    One of the greatest unresolved questions in aging biology is determining the genetic basis of interspecies longevity variation. Gene duplication is often the key to understanding the origin and evolution of important Eutherian phenotypes. We systematically identified longevity-associated genes in model organisms that duplicated throughout Eutherian evolution. Longevity-associated gene families have a marginally significantly higher rate of duplication compared to non-longevity-associated gene families. Anti-longevity-associated gene families have significantly increased rate of duplication compared to pro-longevity gene families and are enriched in neurodegenerative disease categories. Conversely, duplicated pro-longevity-associated gene families are enriched in cell cycle genes. There is a cluster of longevity-associated gene families that expanded solely in long-lived species that is significantly enriched in pathways relating to 3-UTR-mediated translational regulation, metabolism of proteins and gene expression, pathways that have the potential to affect longevity. The identification of a gene cluster that duplicated solely in long-lived species involved in such fundamental processes provides a promising avenue for further exploration of Eutherian longevity evolution. PMID:27378378

  5. Dynamic regulation of PGC-1α localization and turnover implicates mitochondrial adaptation in calorie restriction and the stress response

    PubMed Central

    Anderson, Rozalyn M; Barger, Jamie L; Edwards, Michael G; Braun, Kristina H; O’Connor, Clare E; Prolla, Tomas A; Weindruch, Richard

    2008-01-01

    There is increasing evidence that longevity and stress resistance are connected, but the mechanism is unclear. We report that mitochondria are regulated in response to oxidative stress and calorie restriction through a shared mechanism involving peroxisome proliferator-activated receptor-γ co-activator 1α (PGC-1α). We demonstrate that PGC-1α subcellular distribution is regulated, and its transcriptional activity is promoted through SIRT1-dependent nuclear accumulation. In addition, the duration of PGC-1α activity is regulated by glycogen synthase kinase beta (GSK3β), which targets PGC-1α for intranuclear proteasomal degradation. This mechanism of regulation permits the rapidity and persistence of PGC-1α activation to be independently controlled. We provide evidence that this pathway of PGC-1α regulation occurs in vivo in mice, both in the oxidative stress response and with calorie restriction. Our data show how mitochondrial function may be adapted in response to external stimuli, and support the concept that such adaptation is critically involved in cellular survival and in lifespan extension by calorie restriction. PMID:18031569

  6. Neuroactive steroids and stress axis regulation: Pregnancy and beyond.

    PubMed

    Brunton, Paula J

    2016-06-01

    The hypothalamo-pituitary-adrenal (HPA) axis plays a critical role in regulating responses to stress and long term dysregulation of the HPA axis is associated with higher rates of mood disorders. There are circumstances where the HPA axis is more or less responsive to stress. For example, during late pregnancy ACTH and corticosterone responses to stress are markedly suppressed, whereas in offspring born to mothers that experienced repeated stress during pregnancy, the HPA axis is hyper-responsive to stress. Neuroactive steroids such as allopregnanolone, tetrahydrodeoxycorticosterone (THDOC) and androstanediol can modulate HPA axis activity and concentrations of some neuroactive steroids in the brain are altered during pregnancy and following stress. Thus, here altered neurosteroidogenesis is proposed as a mechanism that could underpin the dynamic changes in HPA axis regulation typically observed in late pregnant and in prenatally stressed individuals. In support of this hypothesis, evidence in rats demonstrates that elevated levels of allopregnanolone in pregnancy induce a central inhibitory opioid mechanism that serves to minimize stress-induced HPA axis activity. Conversely, in prenatally stressed rodents, where HPA axis stress responses are enhanced, evidence indicates the capacity of the brain for neurosteroidogenesis is reduced. Understanding the mechanisms involved in adaptations in HPA axis regulation may provide insights for manipulating stress sensitivity and for developing therapies for stress-related disorders in humans. PMID:26259885

  7. RNA binding protein Pub1p regulates glycerol production and stress tolerance by controlling Gpd1p activity during winemaking.

    PubMed

    Orozco, Helena; Sepúlveda, Ana; Picazo, Cecilia; Matallana, Emilia; Aranda, Agustín

    2016-06-01

    Glycerol is a key yeast metabolite in winemaking because it contributes to improve the organoleptic properties of wine. It is also a cellular protective molecule that enhances the tolerance of yeasts to osmotic stress and promotes longevity. Thus, its production increases by genetic manipulation, which is of biotechnological and basic interest. Glycerol is produced by diverting glycolytic glyceraldehyde-3-phosphate through the action of glycerol-3-phosphate dehydrogenase (coded by genes GPD1 and GPD2). Here, we demonstrate that RNA-binding protein Pub1p regulates glycerol production by controlling Gpd1p activity. Its deletion does not alter GPD1 mRNA levels, but protein levels and enzymatic activity increase, which explains the higher intracellular glycerol concentration and greater tolerance to osmotic stress of the pub1∆ mutant. PUB1 deletion also enhances the activity of nicotinamidase, a longevity-promoting enzyme. Both enzymatic activities are partially located in peroxisomes, and we detected peroxisome formation during wine fermentation. The role of Pub1p in life span control depends on nutrient conditions and is related with the TOR pathway, and a major connection between RNA metabolism and the nutrient signaling response is established. PMID:26846624

  8. Effects of Caenorhabditis elegans sgk-1 mutations on lifespan, stress resistance, and DAF-16/FoxO regulation.

    PubMed

    Chen, Albert Tzong-Yang; Guo, Chunfang; Dumas, Kathleen J; Ashrafi, Kaveh; Hu, Patrick J

    2013-10-01

    The AGC family serine-threonine kinases Akt and Sgk are similar in primary amino acid sequence and in vitro substrate specificity, and both kinases are thought to directly phosphorylate and inhibit FoxO transcription factors. In the nematode Caenorhabditis elegans, it is well established that AKT-1 controls dauer arrest and lifespan by regulating the subcellular localization of the FoxO transcription factor DAF-16. SGK-1 is thought to act similarly to AKT-1 in lifespan control by phosphorylating and inhibiting the nuclear translocation of DAF-16/FoxO. Using sgk-1 null and gain-of-function mutants, we now provide multiple lines of evidence indicating that AKT-1 and SGK-1 influence C. elegans lifespan, stress resistance, and DAF-16/FoxO activity in fundamentally different ways. Whereas AKT-1 shortens lifespan, SGK-1 promotes longevity in a DAF-16-/FoxO-dependent manner. In contrast to AKT-1, which reduces resistance to multiple stresses, SGK-1 promotes resistance to oxidative stress and ultraviolet radiation but inhibits thermotolerance. Analysis of several DAF-16/FoxO target genes that are repressed by AKT-1 reveals that SGK-1 represses a subset of these genes while having little influence on the expression of others. Accordingly, unlike AKT-1, which promotes the cytoplasmic sequestration of DAF-16/FoxO, SGK-1 does not influence DAF-16/FoxO subcellular localization. Thus, in spite of their similar in vitro substrate specificities, Akt and Sgk influence longevity, stress resistance, and FoxO activity through distinct mechanisms in vivo. Our findings highlight the need for a re-evaluation of current paradigms of FoxO regulation by Sgk. PMID:23786484

  9. Regulation of Vascular Endothelium Inflammatory Signalling by Shear Stress.

    PubMed

    Zakkar, Mustafa; Angelini, Gianni D; Emanueli, Costanza

    2016-01-01

    The vascular endothelium plays a pivotal role in regulating vascular homeostasis. Blood flow exerts several mechanical forces on the luminal surface of the Endothelial Cell (EC) including pressure, circumferential stretch, and shear stress. It is widely believed that shear stress plays a central role in regulating EC inflammatory responses and the pathogenesis of atherosclerosis. High shear stress can induce an antiinflammatory status in EC, which is partially mediated by the production of proteins and transcription factors able to suppress different proinflammatory signalling pathways. In this review, we summarise the available evidence regarding the effect of shear stress on vascular EC and smooth muscle cells, the regulation of MAPK and NF-κB including the production of different negative regulators of inflammation such as MKP-1 and NRF2, and the production of microRNAs. We also discuss the possible links between shear stress and the development of atherosclerosis. PMID:26638798

  10. The Plant Heat Stress Transcription Factors (HSFs): Structure, Regulation, and Function in Response to Abiotic Stresses

    PubMed Central

    Guo, Meng; Liu, Jin-Hong; Ma, Xiao; Luo, De-Xu; Gong, Zhen-Hui; Lu, Ming-Hui

    2016-01-01

    Abiotic stresses such as high temperature, salinity, and drought adversely affect the survival, growth, and reproduction of plants. Plants respond to such unfavorable changes through developmental, physiological, and biochemical ways, and these responses require expression of stress-responsive genes, which are regulated by a network of transcription factors (TFs), including heat stress transcription factors (HSFs). HSFs play a crucial role in plants response to several abiotic stresses by regulating the expression of stress-responsive genes, such as heat shock proteins (Hsps). In this review, we describe the conserved structure of plant HSFs, the identification of HSF gene families from various plant species, their expression profiling under abiotic stress conditions, regulation at different levels and function in abiotic stresses. Despite plant HSFs share highly conserved structure, their remarkable diversification across plants reflects their numerous functions as well as their integration into the complex stress signaling and response networks, which can be employed in crop improvement strategies via biotechnological intervention. PMID:26904076

  11. Endoplasmic reticulum: ER stress regulates mitochondrial bioenergetics

    PubMed Central

    Bravo, Roberto; Gutierrez, Tomás; Paredes, Felipe; Gatica, Damián; Rodriguez, Andrea E.; Pedrozo, Zully; Chiong, Mario; Parra, Valentina; Quest, Andrew F.G.; Rothermel, Beverly A.; Lavandero, Sergio

    2014-01-01

    Endoplasmic reticulum (ER) stress activates an adaptive unfolded protein response (UPR) that facilitates cellular repair, however, under prolonged ER stress, the UPR can ultimately trigger apoptosis thereby terminating damaged cells. The molecular mechanisms responsible for execution of the cell death program are relatively well characterized, but the metabolic events taking place during the adaptive phase of ER stress remain largely undefined. Here we discuss emerging evidence regarding the metabolic changes that occur during the onset of ER stress and how ER influences mitochondrial function through mechanisms involving calcium transfer, thereby facilitating cellular adaptation. Finally, we highlight how dysregulation of ER–mitochondrial calcium homeostasis during prolonged ER stress is emerging as a novel mechanism implicated in the onset of metabolic disorders. PMID:22064245

  12. Endoplasmic reticulum: ER stress regulates mitochondrial bioenergetics.

    PubMed

    Bravo, Roberto; Gutierrez, Tomás; Paredes, Felipe; Gatica, Damián; Rodriguez, Andrea E; Pedrozo, Zully; Chiong, Mario; Parra, Valentina; Quest, Andrew F G; Rothermel, Beverly A; Lavandero, Sergio

    2012-01-01

    Endoplasmic reticulum (ER) stress activates an adaptive unfolded protein response (UPR) that facilitates cellular repair, however, under prolonged ER stress, the UPR can ultimately trigger apoptosis thereby terminating damaged cells. The molecular mechanisms responsible for execution of the cell death program are relatively well characterized, but the metabolic events taking place during the adaptive phase of ER stress remain largely undefined. Here we discuss emerging evidence regarding the metabolic changes that occur during the onset of ER stress and how ER influences mitochondrial function through mechanisms involving calcium transfer, thereby facilitating cellular adaptation. Finally, we highlight how dysregulation of ER-mitochondrial calcium homeostasis during prolonged ER stress is emerging as a novel mechanism implicated in the onset of metabolic disorders. PMID:22064245

  13. Regulation of autophagy in oxygen-dependent cellular stress.

    PubMed

    Ryter, Stefan W; Choi, Augustine M K

    2013-01-01

    Oxidative stress caused by supraphysiological production of reactive oxygen species (ROS), can cause cellular injury associated with protein and lipid oxidation, DNA damage, and mitochondrial dysfunction. The cellular responses triggered by oxidative stress include the altered regulation of signaling pathways that culminate in the regulation of cell survival or cell death pathways. Recent studies suggest that autophagy, a cellular homeostatic process that governs the turnover of damaged organelles and proteins, may represent a general cellular and tissue response to oxidative stress. The autophagic pathway involves the encapsulation of substrates in double-membraned vesicles, which are subsequently delivered to the lysosome for enzymatic degradation and recycling of metabolic precursors. Autophagy may play multifunctional roles in cellular adaptation to stress, by maintaining mitochondrial integrity, and removing damaged proteins. Additionally, autophagy may play important roles in the regulation of inflammation and immune function. Modulation of the autophagic pathway has been reported in cell culture models of oxidative stress, including altered states of oxygen tension (i.e., hypoxia, hyperoxia), and exposure to oxidants. Furthermore, proteins that regulate autophagy may be subject to redox regulation. The heme oxygenase- 1 (HO)-1 enzyme system may have a role in the regulation of autophagy. Recent studies suggest that carbon monoxide (CO), a reaction product of HO activity which can alter mitochondrial function, may induce autophagy in cultured epithelial cells. In conclusion, current research suggests a central role for autophagy as a mammalian oxidative stress response and its interrelationship to other stress defense systems. PMID:23092322

  14. Longevity of Taft Joints of Superficially Mounted Construction Parts in Thermally Alternating Stress with Regard to the Significance of Elastic, Plastic and Creep Parts

    NASA Astrophysics Data System (ADS)

    Warnke, Andreas

    1999-01-01

    The goal of this study is the refinement of the technique of low-frequency fatigue analyses of a Taft joint through computer simulation, in order to obtain, in the shortest time possible, a more precise expression of their longevity. To answer the central query, 'how long does the Taft joint hold?', there exists a series of concomitant questions, around which the study centers: on what kind of Taft joint longevity can one count; how are the Taft joint data dependent on mechanical tension, time, and temperature; which conditions promote the ideal results; what must be taken into account during the cross-linkage of the Taft joint for finite element analysis; which temperature should be chosen in order to re-portray the themocycles in a low-frequency fatigue analysis as realistically as possible; and locating the critical geometric places within the Taft joint.

  15. The Cell Non-Autonomous Nature of Electron Transport Chain-Mediated Longevity

    PubMed Central

    Durieux, Jenni; Wolff, Suzanne; Dillin, Andrew

    2011-01-01

    Summary The life span of C. elegans can be increased via reduced function of the mitochondria; however, the extent to which mitochondrial alteration in a single, distinct tissue may influence aging in the whole organism remains unknown. We addressed this question by asking whether manipulations to ETC function can modulate aging in a cell non-autonomous fashion. We report that the alteration of mitochondrial function in key tissues is essential for establishing and maintaining a pro-longevity cue. We find that regulators of mitochondrial stress responses are essential and specific genetic requirements for the electron transport chain (ETC) longevity pathway. Strikingly, we find that mitochondrial perturbation in one tissue is perceived and acted upon by the mitochondrial stress response pathway in a distal tissue. These results suggest that mitochondria may establish and perpetuate the rate of aging for the whole organism independent of cell-autonomous functions. PMID:21215371

  16. Substrate stress relaxation regulates cell spreading

    PubMed Central

    Chaudhuri, Ovijit; Gu, Luo; Darnell, Max; Klumpers, Darinka; Bencherif, Sidi A.; Weaver, James C.; Huebsch, Nathaniel; Mooney, David J

    2015-01-01

    Studies of cellular mechanotransduction have converged upon the idea that cells sense extracellular matrix (ECM) elasticity by gauging resistance to the traction forces they exert on the ECM. However, these studies typically utilize purely elastic materials as substrates, whereas physiological ECM are viscoelastic, and exhibit stress relaxation, so that cellular traction forces exerted by cells remodel the ECM. Here we investigate the influence of ECM stress relaxation on cell behavior through computational modeling and cellular experiments. Surprisingly, both our computational model and experiments find that spreading for cells cultured on soft substrates that exhibit stress relaxation is greater than cells spreading on elastic substrates of the same modulus, but similar to that of cells spreading on stiffer elastic substrates. These findings challenge the current view of how cells sense and respond to the ECM. PMID:25695512

  17. Substrate stress relaxation regulates cell spreading.

    PubMed

    Chaudhuri, Ovijit; Gu, Luo; Darnell, Max; Klumpers, Darinka; Bencherif, Sidi A; Weaver, James C; Huebsch, Nathaniel; Mooney, David J

    2015-01-01

    Studies of cellular mechanotransduction have converged upon the idea that cells sense extracellular matrix (ECM) elasticity by gauging resistance to the traction forces they exert on the ECM. However, these studies typically utilize purely elastic materials as substrates, whereas physiological ECMs are viscoelastic, and exhibit stress relaxation, so that cellular traction forces exerted by cells remodel the ECM. Here we investigate the influence of ECM stress relaxation on cell behaviour through computational modelling and cellular experiments. Surprisingly, both our computational model and experiments find that spreading for cells cultured on soft substrates that exhibit stress relaxation is greater than cells spreading on elastic substrates of the same modulus, but similar to that of cells spreading on stiffer elastic substrates. These findings challenge the current view of how cells sense and respond to the ECM. PMID:25695512

  18. ROS Regulation During Abiotic Stress Responses in Crop Plants

    PubMed Central

    You, Jun; Chan, Zhulong

    2015-01-01

    Abiotic stresses such as drought, cold, salt and heat cause reduction of plant growth and loss of crop yield worldwide. Reactive oxygen species (ROS) including hydrogen peroxide (H2O2), superoxide anions (O2•-), hydroxyl radical (OH•) and singlet oxygen (1O2) are by-products of physiological metabolisms, and are precisely controlled by enzymatic and non-enzymatic antioxidant defense systems. ROS are significantly accumulated under abiotic stress conditions, which cause oxidative damage and eventually resulting in cell death. Recently, ROS have been also recognized as key players in the complex signaling network of plants stress responses. The involvement of ROS in signal transduction implies that there must be coordinated function of regulation networks to maintain ROS at non-toxic levels in a delicate balancing act between ROS production, involving ROS generating enzymes and the unavoidable production of ROS during basic cellular metabolism, and ROS-scavenging pathways. Increasing evidence showed that ROS play crucial roles in abiotic stress responses of crop plants for the activation of stress-response and defense pathways. More importantly, manipulating ROS levels provides an opportunity to enhance stress tolerances of crop plants under a variety of unfavorable environmental conditions. This review presents an overview of current knowledge about homeostasis regulation of ROS in crop plants. In particular, we summarize the essential proteins that are involved in abiotic stress tolerance of crop plants through ROS regulation. Finally, the challenges toward the improvement of abiotic stress tolerance through ROS regulation in crops are discussed. PMID:26697045

  19. 77 FR 66566 - Stress Testing of Regulated Entities

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-11-06

    ..., FHFA published for comment in the Federal Register a proposed rule, and invited comments. See 77 FR...; ] FEDERAL HOUSING FINANCE AGENCY 12 CFR Part 1238 RIN 2590-AA47 Stress Testing of Regulated Entities AGENCY... notice of proposed rulemaking for public comment concerning stress testing of the Federal...

  20. 77 FR 5443 - Longevity Annuity Contracts

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-02-03

    ... for Participants and Beneficiaries in Retirement Plans in the Federal Register (75 FR 5253). That... whom a longevity annuity contract is purchased under these plans and IRAs (and their beneficiaries... of a public hearing on these proposed regulations. DATES: Written or electronic comments must...

  1. tRNA modifications regulate translation during cellular stress

    PubMed Central

    Gu, Chen; Begley, Thomas J.; Dedon, Peter C.

    2014-01-01

    The regulation of gene expression in response to stress is an essential cellular protection mechanism. Recent advances in tRNA modification analysis and genome-based codon bias analytics have facilitated studies that lead to a novel model for translational control, with translation elongation dynamically regulated during stress responses. Stress-induced increases in specific anticodon wobble bases are required for the optimal translation of stress response transcripts that are significantly biased in the use of degenerate codons keyed to these modified tRNA bases. These findings led us to introduce the notion of tRNA modification tunable transcripts (MoTTs – transcripts whose translation is regulated by tRNA modifications), which are identifiable using genome-wide codon counting algorithms. In support of this general model of translational control of stress response, studies making use of detailed measures of translation, tRNA methyltransferase mutants, and computational and mass spectrometry approaches reveal that stress reprograms tRNA modifications to translationally regulate MoTTs linked to arginine and leucine codons, which helps cells survive insults by damaging agents. These studies highlight how tRNA methyltransferase activities and MoTTs are key components of the cellular stress response. PMID:25304425

  2. Life in the cold: links between mammalian hibernation and longevity.

    PubMed

    Wu, Cheng-Wei; Storey, Kenneth B

    2016-02-01

    The biological process of aging is the primary determinant of lifespan, but the factors that influence the rate of aging are not yet clearly understood and remain a challenging question. Mammals are characterized by >100-fold differences in maximal lifespan, influenced by relative variances in body mass and metabolic rate. Recent discoveries have identified long-lived mammalian species that deviate from the expected longevity quotient. A commonality among many long-lived species is the capacity to undergo metabolic rate depression, effectively re-programming normal metabolism in response to extreme environmental stress and enter states of torpor or hibernation. This stress tolerant phenotype often involves a reduction in overall metabolic rate to just 1-5% of the normal basal rate as well as activation of cytoprotective responses. At the cellular level, major energy savings are achieved via coordinated suppression of many ATP-expensive cell functions; e.g. global rates of protein synthesis are strongly reduced via inhibition of the insulin signaling axis. At the same time, various studies have shown activation of stress survival signaling during hibernation including up-regulation of protein chaperones, increased antioxidant defenses, and transcriptional activation of pro-survival signaling such as the FOXO and p53 pathways. Many similarities and parallels exist between hibernation phenotypes and different long-lived models, e.g. signal transduction pathways found to be commonly regulated during hibernation are also known to induce lifespan extension in animals such as Drosophila melanogaster and Caenorhabditis elegans. In this review, we highlight some of the molecular mechanisms that promote longevity in classic aging models C. elegans, Drosophila, and mice, while providing a comparative analysis to how they are regulated during mammalian hibernation. PMID:26820181

  3. Mechanical stress regulation of plant growth and development

    NASA Technical Reports Server (NTRS)

    Mitchell, C. A.; Myers, P. N.

    1995-01-01

    The authors introduce the chapter with a discussion of lessons from nature, agriculture, and landscapes; terms and definitions; and an historical perspective of mechanical stress regulation of plant growth and development. Topics include developmental responses to mechanical stress; mechanical stress-environment interactions; metabolic, productivity, and compositional changes; hormonal involvement; mechanoperception and early transduction mechanisms; applications in agriculture; and research implications. The discussion of hormonal involvement in mechanical stress physiology includes ethylene, auxin, gibberellins, and other phytohormones. The discussion of applications in agriculture examines windbreaks, nursery practices, height control and conditioning, and enhancement of growth and productivity. Implications for research are related to handling plant materials, space biology, and future research needs.

  4. Heterogeneity in expected longevities.

    PubMed

    Pijoan-Mas, Josep; Ríos-Rull, José-Víctor

    2014-12-01

    We develop a new methodology to compute differences in the expected longevity of individuals of a given cohort who are in different socioeconomic groups at a certain age. We address the two main problems associated with the standard use of life expectancy: (1) that people's socioeconomic characteristics change, and (2) that mortality has decreased over time. Our methodology uncovers substantial heterogeneity in expected longevities, yet much less heterogeneity than what arises from the naive application of life expectancy formulae. We decompose the longevity differences into differences in health at age 50, differences in the evolution of health with age, and differences in mortality conditional on health. Remarkably, education, wealth, and income are health-protecting but have very little impact on two-year mortality rates conditional on health. Married people and nonsmokers, however, benefit directly in their immediate mortality. Finally, we document an increasing time trend of the socioeconomic gradient of longevity in the period 1992-2008, and we predict an increase in the socioeconomic gradient of mortality rates for the coming years. PMID:25391225

  5. Novel loci and pathways significantly associated with longevity.

    PubMed

    Zeng, Yi; Nie, Chao; Min, Junxia; Liu, Xiaomin; Li, Mengmeng; Chen, Huashuai; Xu, Hanshi; Wang, Mingbang; Ni, Ting; Li, Yang; Yan, Han; Zhang, Jin-Pei; Song, Chun; Chi, Li-Qing; Wang, Han-Ming; Dong, Jie; Zheng, Gu-Yan; Lin, Li; Qian, Feng; Qi, Yanwei; Liu, Xiao; Cao, Hongzhi; Wang, Yinghao; Zhang, Lijuan; Li, Zhaochun; Zhou, Yufeng; Wang, Yan; Lu, Jiehua; Li, Jianxin; Qi, Ming; Bolund, Lars; Yashin, Anatoliy; Land, Kenneth C; Gregory, Simon; Yang, Ze; Gottschalk, William; Tao, Wei; Wang, Jian; Wang, Jun; Xu, Xun; Bae, Harold; Nygaard, Marianne; Christiansen, Lene; Christensen, Kaare; Franceschi, Claudio; Lutz, Michael W; Gu, Jun; Tan, Qihua; Perls, Thomas; Sebastiani, Paola; Deelen, Joris; Slagboom, Eline; Hauser, Elizabeth; Xu, Huji; Tian, Xiao-Li; Yang, Huanming; Vaupel, James W

    2016-01-01

    Only two genome-wide significant loci associated with longevity have been identified so far, probably because of insufficient sample sizes of centenarians, whose genomes may harbor genetic variants associated with health and longevity. Here we report a genome-wide association study (GWAS) of Han Chinese with a sample size 2.7 times the largest previously published GWAS on centenarians. We identified 11 independent loci associated with longevity replicated in Southern-Northern regions of China, including two novel loci (rs2069837-IL6; rs2440012-ANKRD20A9P) with genome-wide significance and the rest with suggestive significance (P < 3.65 × 10(-5)). Eight independent SNPs overlapped across Han Chinese, European and U.S. populations, and APOE and 5q33.3 were replicated as longevity loci. Integrated analysis indicates four pathways (starch, sucrose and xenobiotic metabolism; immune response and inflammation; MAPK; calcium signaling) highly associated with longevity (P ≤ 0.006) in Han Chinese. The association with longevity of three of these four pathways (MAPK; immunity; calcium signaling) is supported by findings in other human cohorts. Our novel finding on the association of starch, sucrose and xenobiotic metabolism pathway with longevity is consistent with the previous results from Drosophilia. This study suggests protective mechanisms including immunity and nutrient metabolism and their interactions with environmental stress play key roles in human longevity. PMID:26912274

  6. Novel loci and pathways significantly associated with longevity

    PubMed Central

    Zeng, Yi; Nie, Chao; Min, Junxia; Liu, Xiaomin; Li, Mengmeng; Chen, Huashuai; Xu, Hanshi; Wang, Mingbang; Ni, Ting; Li, Yang; Yan, Han; Zhang, Jin-Pei; Song, Chun; Chi, Li-Qing; Wang, Han-Ming; Dong, Jie; Zheng, Gu-Yan; Lin, Li; Qian, Feng; Qi, Yanwei; Liu, Xiao; Cao, Hongzhi; Wang, Yinghao; Zhang, Lijuan; Li, Zhaochun; Zhou, Yufeng; Wang, Yan; Lu, Jiehua; Li, Jianxin; Qi, Ming; Bolund, Lars; Yashin, Anatoliy; Land, Kenneth C.; Gregory, Simon; Yang, Ze; Gottschalk, William; Tao, Wei; Wang, Jian; Wang, Jun; Xu, Xun; Bae, Harold; Nygaard, Marianne; Christiansen, Lene; Christensen, Kaare; Franceschi, Claudio; Lutz, Michael W.; Gu, Jun; Tan, Qihua; Perls, Thomas; Sebastiani, Paola; Deelen, Joris; Slagboom, Eline; Hauser, Elizabeth; Xu, Huji; Tian, Xiao-Li; Yang, Huanming; Vaupel, James W.

    2016-01-01

    Only two genome-wide significant loci associated with longevity have been identified so far, probably because of insufficient sample sizes of centenarians, whose genomes may harbor genetic variants associated with health and longevity. Here we report a genome-wide association study (GWAS) of Han Chinese with a sample size 2.7 times the largest previously published GWAS on centenarians. We identified 11 independent loci associated with longevity replicated in Southern-Northern regions of China, including two novel loci (rs2069837-IL6; rs2440012-ANKRD20A9P) with genome-wide significance and the rest with suggestive significance (P < 3.65 × 10−5). Eight independent SNPs overlapped across Han Chinese, European and U.S. populations, and APOE and 5q33.3 were replicated as longevity loci. Integrated analysis indicates four pathways (starch, sucrose and xenobiotic metabolism; immune response and inflammation; MAPK; calcium signaling) highly associated with longevity (P ≤ 0.006) in Han Chinese. The association with longevity of three of these four pathways (MAPK; immunity; calcium signaling) is supported by findings in other human cohorts. Our novel finding on the association of starch, sucrose and xenobiotic metabolism pathway with longevity is consistent with the previous results from Drosophilia. This study suggests protective mechanisms including immunity and nutrient metabolism and their interactions with environmental stress play key roles in human longevity. PMID:26912274

  7. GABAB(1) receptor subunit isoforms differentially regulate stress resilience.

    PubMed

    O'Leary, Olivia F; Felice, Daniela; Galimberti, Stefano; Savignac, Hélène M; Bravo, Javier A; Crowley, Tadhg; El Yacoubi, Malika; Vaugeois, Jean-Marie; Gassmann, Martin; Bettler, Bernhard; Dinan, Timothy G; Cryan, John F

    2014-10-21

    Stressful life events increase the susceptibility to developing psychiatric disorders such as depression; however, many individuals are resilient to such negative effects of stress. Determining the neurobiology underlying this resilience is instrumental to the development of novel and more effective treatments for stress-related psychiatric disorders. GABAB receptors are emerging therapeutic targets for the treatment of stress-related disorders such as depression. These receptors are predominantly expressed as heterodimers of a GABAB(2) subunit with either a GABAB(1a) or a GABAB(1b) subunit. Here we show that mice lacking the GABAB(1b) receptor isoform are more resilient to both early-life stress and chronic psychosocial stress in adulthood, whereas mice lacking GABAB(1a) receptors are more susceptible to stress-induced anhedonia and social avoidance compared with wild-type mice. In addition, increased hippocampal expression of the GABAB(1b) receptor subunit is associated with a depression-like phenotype in the helpless H/Rouen genetic mouse model of depression. Stress resilience in GABAB(1b)(-/-) mice is coupled with increased proliferation and survival of newly born cells in the adult ventral hippocampus and increased stress-induced c-Fos activation in the hippocampus following early-life stress. Taken together, the data suggest that GABAB(1) receptor subunit isoforms differentially regulate the deleterious effects of stress and, thus, may be important therapeutic targets for the treatment of depression. PMID:25288769

  8. Intestinal Insulin Signaling Encodes Two Different Molecular Mechanisms for the Shortened Longevity Induced by Graphene Oxide in Caenorhabditis elegans

    NASA Astrophysics Data System (ADS)

    Zhao, Yunli; Yang, Ruilong; Rui, Qi; Wang, Dayong

    2016-04-01

    Graphene oxide (GO) has been shown to cause multiple toxicities in various organisms. However, the underlying molecular mechanisms for GO-induced shortened longevity are still unclear. We employed Caenorhabditis elegans to investigate the possible involvement of insulin signaling pathway in the control of GO toxicity and its underlying molecular mechanisms. Mutation of daf-2, age-1, akt-1, or akt-2 gene induced a resistant property of nematodes to GO toxicity, while mutation of daf-16 gene led to a susceptible property of nematodes to GO toxicity, suggesting that GO may dysregulate the functions of DAF-2/IGF-1 receptor, AGE-1, AKT-1 and AKT-2-mediated kinase cascade, and DAF-16/FOXO transcription factor. Genetic interaction analysis suggested the involvement of signaling cascade of DAF-2-AGE-1-AKT-1/2-DAF-16 in the control of GO toxicity on longevity. Moreover, intestinal RNA interference (RNAi) analysis demonstrated that GO reduced longevity by affecting the functions of signaling cascade of DAF-2-AGE-1-AKT-1/2-DAF-16 in the intestine. DAF-16 could also regulate GO toxicity on longevity by functioning upstream of SOD-3, which encodes an antioxidation system that prevents the accumulation of oxidative stress. Therefore, intestinal insulin signaling may encode two different molecular mechanisms responsible for the GO toxicity in inducing the shortened longevity. Our results highlight the key role of insulin signaling pathway in the control of GO toxicity in organisms.

  9. Intestinal Insulin Signaling Encodes Two Different Molecular Mechanisms for the Shortened Longevity Induced by Graphene Oxide in Caenorhabditis elegans.

    PubMed

    Zhao, Yunli; Yang, Ruilong; Rui, Qi; Wang, Dayong

    2016-01-01

    Graphene oxide (GO) has been shown to cause multiple toxicities in various organisms. However, the underlying molecular mechanisms for GO-induced shortened longevity are still unclear. We employed Caenorhabditis elegans to investigate the possible involvement of insulin signaling pathway in the control of GO toxicity and its underlying molecular mechanisms. Mutation of daf-2, age-1, akt-1, or akt-2 gene induced a resistant property of nematodes to GO toxicity, while mutation of daf-16 gene led to a susceptible property of nematodes to GO toxicity, suggesting that GO may dysregulate the functions of DAF-2/IGF-1 receptor, AGE-1, AKT-1 and AKT-2-mediated kinase cascade, and DAF-16/FOXO transcription factor. Genetic interaction analysis suggested the involvement of signaling cascade of DAF-2-AGE-1-AKT-1/2-DAF-16 in the control of GO toxicity on longevity. Moreover, intestinal RNA interference (RNAi) analysis demonstrated that GO reduced longevity by affecting the functions of signaling cascade of DAF-2-AGE-1-AKT-1/2-DAF-16 in the intestine. DAF-16 could also regulate GO toxicity on longevity by functioning upstream of SOD-3, which encodes an antioxidation system that prevents the accumulation of oxidative stress. Therefore, intestinal insulin signaling may encode two different molecular mechanisms responsible for the GO toxicity in inducing the shortened longevity. Our results highlight the key role of insulin signaling pathway in the control of GO toxicity in organisms. PMID:27040644

  10. Intestinal Insulin Signaling Encodes Two Different Molecular Mechanisms for the Shortened Longevity Induced by Graphene Oxide in Caenorhabditis elegans

    PubMed Central

    Zhao, Yunli; Yang, Ruilong; Rui, Qi; Wang, Dayong

    2016-01-01

    Graphene oxide (GO) has been shown to cause multiple toxicities in various organisms. However, the underlying molecular mechanisms for GO-induced shortened longevity are still unclear. We employed Caenorhabditis elegans to investigate the possible involvement of insulin signaling pathway in the control of GO toxicity and its underlying molecular mechanisms. Mutation of daf-2, age-1, akt-1, or akt-2 gene induced a resistant property of nematodes to GO toxicity, while mutation of daf-16 gene led to a susceptible property of nematodes to GO toxicity, suggesting that GO may dysregulate the functions of DAF-2/IGF-1 receptor, AGE-1, AKT-1 and AKT-2-mediated kinase cascade, and DAF-16/FOXO transcription factor. Genetic interaction analysis suggested the involvement of signaling cascade of DAF-2-AGE-1-AKT-1/2-DAF-16 in the control of GO toxicity on longevity. Moreover, intestinal RNA interference (RNAi) analysis demonstrated that GO reduced longevity by affecting the functions of signaling cascade of DAF-2-AGE-1-AKT-1/2-DAF-16 in the intestine. DAF-16 could also regulate GO toxicity on longevity by functioning upstream of SOD-3, which encodes an antioxidation system that prevents the accumulation of oxidative stress. Therefore, intestinal insulin signaling may encode two different molecular mechanisms responsible for the GO toxicity in inducing the shortened longevity. Our results highlight the key role of insulin signaling pathway in the control of GO toxicity in organisms. PMID:27040644

  11. Interorganelle signaling is a determinant of longevity in Saccharomyces cerevisiae.

    PubMed Central

    Kirchman, P A; Kim, S; Lai, C Y; Jazwinski, S M

    1999-01-01

    Replicative capacity, which is the number of times an individual cell divides, is the measure of longevity in the yeast Saccharomyces cerevisiae. In this study, a process that involves signaling from the mitochondrion to the nucleus, called retrograde regulation, is shown to determine yeast longevity, and its induction resulted in postponed senescence. Activation of retrograde regulation, by genetic and environmental means, correlated with increased replicative capacity in four different S. cerevisiae strains. Deletion of a gene required for the retrograde response, RTG2, eliminated the increased replicative capacity. RAS2, a gene previously shown to influence longevity in yeast, interacts with retrograde regulation in setting yeast longevity. The molecular mechanism of aging elucidated here parallels the results of genetic studies of aging in nematodes and fruit flies, as well as the caloric restriction paradigm in mammals, and it underscores the importance of metabolic regulation in aging, suggesting a general applicability. PMID:10224252

  12. NRF2 Regulates PINK1 Expression under Oxidative Stress Conditions

    PubMed Central

    Murata, Hitoshi; Takamatsu, Hitoshi; Liu, Sulai; Kataoka, Ken; Huh, Nam-ho; Sakaguchi, Masakiyo

    2015-01-01

    Mutations of the PTEN-induced putative kinase 1 (PINK1) gene are a cause of autosomal recessive forms of Parkinson’s disease. Recent studies have revealed that PINK1 is an essential factor for controlling mitochondrial quality, and that it protects cells from oxidative stresses. Although there has been considerable progress in the elucidation of various aspects of PINK1 protein regulation such as activation, stability and degradation, the transcriptional regulation of PINK1 mRNA under stress conditions remains unclear. In this study, we found that nuclear factor (erythroid-derived 2)-like 2 (NRF2), an antioxidant transcription factor, regulates PINK1 expression under oxidative stress conditions. Damaged mitochondria arising from stress conditions induced NRF2-dependent transcription of the PINK1 gene through production of reactive oxygen species (ROS). Either an ROS scavenger or forced expression of KEAP1, a potent inhibitory partner to NRF2, restricted PINK1 expression induced by activated NRF2. Transcriptionally up-regulated PINK1 diminished oxidative stress-associated cell death. The results indicate that PINK1 expression is positively regulated by NRF2 and that the NRF2-PINK1 signaling axis is deeply involved in cell survival. PMID:26555609

  13. Polyamines function in stress tolerance: from synthesis to regulation

    PubMed Central

    Liu, Ji-Hong; Wang, Wei; Wu, Hao; Gong, Xiaoqing; Moriguchi, Takaya

    2015-01-01

    Plants are challenged by a variety of biotic or abiotic stresses, which can affect their growth and development, productivity, and geographic distribution. In order to survive adverse environmental conditions, plants have evolved various adaptive strategies, among which is the accumulation of metabolites that play protective roles. A well-established example of the metabolites that are involved in stress responses, or stress tolerance, is the low-molecular-weight aliphatic polyamines, including putrescine, spermidine, and spermine. The critical role of polyamines in stress tolerance is suggested by several lines of evidence: firstly, the transcript levels of polyamine biosynthetic genes, as well as the activities of the corresponding enzymes, are induced by stresses; secondly, elevation of endogenous polyamine levels by exogenous supply of polyamines, or overexpression of polyamine biosynthetic genes, results in enhanced stress tolerance; and thirdly, a reduction of endogenous polyamines is accompanied by compromised stress tolerance. A number of studies have demonstrated that polyamines function in stress tolerance largely by modulating the homeostasis of reactive oxygen species (ROS) due to their direct, or indirect, roles in regulating antioxidant systems or suppressing ROS production. The transcriptional regulation of polyamine synthesis by transcription factors is also reviewed here. Meanwhile, future perspectives on polyamine research are also suggested. PMID:26528300

  14. Antemortem stress regulates protein acetylation and glycolysis in postmortem muscle.

    PubMed

    Li, Zhongwen; Li, Xin; Wang, Zhenyu; Shen, Qingwu W; Zhang, Dequan

    2016-07-01

    Although exhaustive research has established that preslaughter stress is a major factor contributing to pale, soft, exudative (PSE) meat, questions remain regarding the biochemistry of postmortem glycolysis. In this study, the influence of preslaughter stress on protein acetylation in relationship to glycolysis was studied. The data show that antemortem swimming significantly enhanced glycolysis and the total acetylated proteins in postmortem longissimus dorsi (LD) muscle of mice. Inhibition of protein acetylation by histone acetyltransferase (HAT) inhibitors eliminated stress induced increase in glycolysis. Inversely, antemortem injection of histone deacetylase (HDAC) inhibitors, trichostatin A (TSA) and nicotinamide (NAM), further increased protein acetylation early postmortem and the glycolysis. These data provide new insight into the biochemistry of postmortem glycolysis by showing that protein acetylation regulates glycolysis, which may participate in the regulation of preslaughter stress on glycolysis in postmortem muscle. PMID:26920270

  15. Epigenetics and the regulation of stress vulnerability and resilience.

    PubMed

    Zannas, A S; West, A E

    2014-04-01

    The human brain has a remarkable capacity to adapt to and learn from a wide range of variations in the environment. However, environmental challenges can also precipitate psychiatric disorders in susceptible individuals. Why any given experience should induce one brain to adapt while another is edged toward psychopathology remains poorly understood. Like all aspects of psychological function, both nature (genetics) and nurture (life experience) sculpt the brain's response to stressful stimuli. Here we review how these two influences intersect at the epigenetic regulation of neuronal gene transcription, and we discuss how the regulation of genomic DNA methylation near key stress-response genes may influence psychological susceptibility or resilience to environmental stressors. Our goal is to offer a perspective on the epigenetics of stress responses that works to bridge the gap between the study of this molecular process in animal models and its potential usefulness for understanding stress vulnerabilities in humans. PMID:24333971

  16. Epigenetics and the regulation of stress vulnerability and resilience

    PubMed Central

    Zannas, Anthony S.; West, Anne E.

    2014-01-01

    The human brain has a remarkable capacity to adapt to and learn from a wide range of variations in the environment. However, environmental challenges can also precipitate psychiatric disorders in susceptible individuals. Why any given experience should induce one brain to adapt while another is edged toward psychopathology remains poorly understood. Like all aspects of psychological function, both nature (genetics) and nurture (life experience) sculpt the brain's response to stressful stimuli. Here we review how these two influences intersect at the epigenetic regulation of neuronal gene transcription, and we discuss how the regulation of genomic DNA methylation near key stress-response genes may influence psychological susceptibility or resilience to environmental stressors. Our goal is to offer a perspective on the epigenetics of stress responses that works to bridge the gap between the study of this molecular process in animal models and its potential usefulness for understanding stress vulnerabilities in humans. PMID:24333971

  17. Transcription Regulation and Membrane Stress Management in Enterobacterial Pathogens.

    PubMed

    Zhang, Nan; Jovanovic, Goran; McDonald, Christopher; Ces, Oscar; Zhang, Xiaodong; Buck, Martin

    2016-01-01

    Transcription regulation in a temporal and conditional manner underpins the lifecycle of enterobacterial pathogens. Upon exposure to a wide array of environmental cues, these pathogens modulate their gene expression via the RNA polymerase and associated sigma factors. Different sigma factors, either involved in general 'house-keeping' or specific responses, guide the RNA polymerase to their cognate promoter DNAs. The major alternative sigma54 factor when activated helps pathogens manage stresses and proliferate in their ecological niches. In this chapter, we review the function and regulation of the sigma54-dependent Phage shock protein (Psp) system-a major stress response when Gram-negative pathogens encounter damages to their inner membranes. We discuss the recent development on mechanisms of gene regulation, signal transduction and stress mitigation in light of different biophysical and biochemical approaches. PMID:27193545

  18. (+/-)-catechin: chemical weapon, antioxidant, or stress regulator?

    PubMed

    Chobot, Vladimir; Huber, Christoph; Trettenhahn, Guenter; Hadacek, Franz

    2009-08-01

    (+/-)-Catechin is a flavan-3-ol that occurs in the organs of many plant species, especially fruits. Health-beneficial effects have been studied extensively, and notable toxic effects have not been found. In contrast, (+/-)-catechin has been implicated as a 'chemical weapon' that is exuded by the roots of Centaurea stoebe, an invasive knapweed of northern America. Recently, this hypothesis has been rejected based on (+/-)-catechin's low phytotoxicity, instability at pH levels higher than 5, and poor recovery from soil. In the current study, (+/-)-catechin did not inhibit the development of white and black mustard to an extent that was comparable to the highly phytotoxic juglone, a naphthoquinone that is allegedly responsible for the allelopathy of the walnut tree. At high stress levels, caused by sub-lethal methanol concentrations in the medium, and a 12 h photoperiod, (+/-)-catechin even attenuated growth retardation. A similar effect was observed when (+/-)-catechin was assayed for brine shrimp mortality. Higher concentrations reduced the mortality caused by toxic concentrations of methanol. Further, when (+/-)-catechin was tested in variants of the deoxyribose degradation assay, it was an efficient scavenger of reactive oxygen species (ROS) when they were present in higher concentrations. This antioxidant effect was enhanced when iron was chelated directly by (+/-)-catechin. Conversely, if iron was chelated to EDTA, pro-oxidative effects were demonstrated at higher concentrations; in this case (+/-)-catechin reduced molecular oxygen and iron to reagents required by the Fenton reaction to produce hydroxyl radicals. A comparison of cyclic voltammograms of (+/-)-catechin with the phytotoxic naphthoquinone juglone indicated similar redox-cycling properties for both compounds although juglone required lower electrochemical potentials to enter redox reactions. In buffer solutions, (+/-)-catechin remained stable at pH 3.6 (vacuole) and decomposed at pH 7.4 (cytoplasm

  19. Defining Molecular Basis for Longevity Traits in Natural Yeast Isolates

    PubMed Central

    Kaya, Alaattin; Ma, Siming; Wasko, Brian; Lee, Mitchell; Kaeberlein, Matt; Gladyshev, Vadim N.

    2016-01-01

    The budding yeast has served as a useful model organism in aging studies, leading to the identification of genetic determinants of longevity, many of which are conserved in higher eukaryotes. However, factors that promote longevity in laboratory setting often have severe fitness disadvantage in the wild. Here, to obtain an unbiased view on longevity regulation we analyzed how replicative lifespan is shaped by transcriptional, translational, metabolic, and morphological factors across 22 wild-type Saccharomyces cerevisiae isolates. We observed significant differences in lifespan across these strains and found that their longevity is strongly associated with up-regulation of oxidative phosphorylation and respiration and down-regulation of amino acid and nitrogen compound biosynthesis. Since calorie restriction and TOR signaling also extend lifespan by adjusting many of the identified pathways, the data suggest that natural plasticity of yeast lifespan is shaped by processes that not only do not impose cost on fitness, but are amenable to dietary intervention. PMID:27030810

  20. Cold stress regulation of gene expression in plants.

    PubMed

    Chinnusamy, Viswanathan; Zhu, Jianhua; Zhu, Jian-Kang

    2007-10-01

    Cold stress adversely affects plant growth and development. Most temperate plants acquire freezing tolerance by a process called cold acclimation. Here, we focus on recent progress in transcriptional, post-transcriptional and post-translational regulation of gene expression that is critical for cold acclimation. Transcriptional regulation is mediated by the inducer of C-repeat binding factor (CBF) expression 1 (ICE1), the CBF transcriptional cascade and CBF-independent regulons during cold acclimation. ICE1 is negatively regulated by ubiquitination-mediated proteolysis and positively regulated by SUMO (small ubiquitin-related modifier) E3 ligase-catalyzed sumoylation. Post-transcriptional regulatory mechanisms, such as pre-mRNA splicing, mRNA export and small RNA-directed mRNA degradation, also play important roles in cold stress responses. PMID:17855156

  1. An Energy-Independent Pro-longevity Function of Triacylglycerol in Yeast.

    PubMed

    Handee, Witawas; Li, Xiaobo; Hall, Kevin W; Deng, Xiexiong; Li, Pan; Benning, Christoph; Williams, Barry L; Kuo, Min-Hao

    2016-02-01

    Intracellular triacylglycerol (TAG) is a ubiquitous energy storage lipid also involved in lipid homeostasis and signaling. Comparatively, little is known about TAG's role in other cellular functions. Here we show a pro-longevity function of TAG in the budding yeast Saccharomyces cerevisiae. In yeast strains derived from natural and laboratory environments a correlation between high levels of TAG and longer chronological lifespan was observed. Increased TAG abundance through the deletion of TAG lipases prolonged chronological lifespan of laboratory strains, while diminishing TAG biosynthesis shortened lifespan without apparently affecting vegetative growth. TAG-mediated lifespan extension was independent of several other known stress response factors involved in chronological aging. Because both lifespan regulation and TAG metabolism are conserved, this cellular pro-longevity function of TAG may extend to other organisms. PMID:26907989

  2. An Energy-Independent Pro-longevity Function of Triacylglycerol in Yeast

    PubMed Central

    Hall, Kevin W.; Deng, Xiexiong; Li, Pan; Benning, Christoph; Williams, Barry L.; Kuo, Min-Hao

    2016-01-01

    Intracellular triacylglycerol (TAG) is a ubiquitous energy storage lipid also involved in lipid homeostasis and signaling. Comparatively, little is known about TAG’s role in other cellular functions. Here we show a pro-longevity function of TAG in the budding yeast Saccharomyces cerevisiae. In yeast strains derived from natural and laboratory environments a correlation between high levels of TAG and longer chronological lifespan was observed. Increased TAG abundance through the deletion of TAG lipases prolonged chronological lifespan of laboratory strains, while diminishing TAG biosynthesis shortened lifespan without apparently affecting vegetative growth. TAG-mediated lifespan extension was independent of several other known stress response factors involved in chronological aging. Because both lifespan regulation and TAG metabolism are conserved, this cellular pro-longevity function of TAG may extend to other organisms. PMID:26907989

  3. Differentially expressed seed aging responsive heat shock protein OsHSP18.2 implicates in seed vigor, longevity and improves germination and seedling establishment under abiotic stress

    PubMed Central

    Kaur, Harmeet; Petla, Bhanu P.; Kamble, Nitin U.; Singh, Ajeet; Rao, Venkateswara; Salvi, Prafull; Ghosh, Shraboni; Majee, Manoj

    2015-01-01

    Small heat shock proteins (sHSPs) are a diverse group of proteins and are highly abundant in plant species. Although majority of these sHSPs were shown to express specifically in seed, their potential function in seed physiology remains to be fully explored. Our proteomic analysis revealed that OsHSP18.2, a class II cytosolic HSP is an aging responsive protein as its abundance significantly increased after artificial aging in rice seeds. OsHSP18.2 transcript was found to markedly increase at the late maturation stage being highly abundant in dry seeds and sharply decreased after germination. Our biochemical study clearly demonstrated that OsHSP18.2 forms homooligomeric complex and is dodecameric in nature and functions as a molecular chaperone. OsHSP18.2 displayed chaperone activity as it was effective in preventing thermal inactivation of Citrate Synthase. Further, to analyze the function of this protein in seed physiology, seed specific Arabidopsis overexpression lines for OsHSP18.2 were generated. Our subsequent functional analysis clearly demonstrated that OsHSP18.2 has ability to improve seed vigor and longevity by reducing deleterious ROS accumulation in seeds. In addition, transformed Arabidopsis seeds also displayed better performance in germination and cotyledon emergence under adverse conditions. Collectively, our work demonstrates that OsHSP18.2 is an aging responsive protein which functions as a molecular chaperone and possibly protect and stabilize the cellular proteins from irreversible damage particularly during maturation drying, desiccation and aging in seeds by restricting ROS accumulation and thereby improves seed vigor, longevity and seedling establishment. PMID:26442027

  4. Differentially expressed seed aging responsive heat shock protein OsHSP18.2 implicates in seed vigor, longevity and improves germination and seedling establishment under abiotic stress.

    PubMed

    Kaur, Harmeet; Petla, Bhanu P; Kamble, Nitin U; Singh, Ajeet; Rao, Venkateswara; Salvi, Prafull; Ghosh, Shraboni; Majee, Manoj

    2015-01-01

    Small heat shock proteins (sHSPs) are a diverse group of proteins and are highly abundant in plant species. Although majority of these sHSPs were shown to express specifically in seed, their potential function in seed physiology remains to be fully explored. Our proteomic analysis revealed that OsHSP18.2, a class II cytosolic HSP is an aging responsive protein as its abundance significantly increased after artificial aging in rice seeds. OsHSP18.2 transcript was found to markedly increase at the late maturation stage being highly abundant in dry seeds and sharply decreased after germination. Our biochemical study clearly demonstrated that OsHSP18.2 forms homooligomeric complex and is dodecameric in nature and functions as a molecular chaperone. OsHSP18.2 displayed chaperone activity as it was effective in preventing thermal inactivation of Citrate Synthase. Further, to analyze the function of this protein in seed physiology, seed specific Arabidopsis overexpression lines for OsHSP18.2 were generated. Our subsequent functional analysis clearly demonstrated that OsHSP18.2 has ability to improve seed vigor and longevity by reducing deleterious ROS accumulation in seeds. In addition, transformed Arabidopsis seeds also displayed better performance in germination and cotyledon emergence under adverse conditions. Collectively, our work demonstrates that OsHSP18.2 is an aging responsive protein which functions as a molecular chaperone and possibly protect and stabilize the cellular proteins from irreversible damage particularly during maturation drying, desiccation and aging in seeds by restricting ROS accumulation and thereby improves seed vigor, longevity and seedling establishment. PMID:26442027

  5. Juvenile stress impairs body temperature regulation and augments anticipatory stress-induced hyperthermia responses in rats.

    PubMed

    Yee, Nicole; Plassmann, Kerstin; Fuchs, Eberhard

    2011-09-01

    Clinical studies have implicated adolescence as an important and vulnerable period during which traumatic experiences can predispose individuals to anxiety and mood disorders. As such, a stress model in juvenile rats (age 27-29 d) was previously developed to investigate the long-term effects of stress exposure during adolescence on behavior and physiology. This paradigm involves exposing rats to different stressors on consecutive days over a 3-day period. Here, we studied the effects of juvenile stress on long-term core body temperature regulation and acute stress-induced hyperthermia (SIH) responses using telemetry. We found no differences between control and juvenile stress rats in anxiety-related behavior on the elevated plus maze, which we attribute to stress associated with surgical implantation of telemetry devices. This highlights the severe impact of surgical stress on the results of subsequent behavioral measurements. Nonetheless, juvenile stress disrupted the circadian rhythmicity of body temperature and decreased circadian amplitude. It also induced chronic hypothermia during the dark phase of the day, when rats are most active. When subjected to acute social defeat stress as adults, juvenile stress had no impact on the SIH response relative to controls. However, 24 h later, juvenile stress rats displayed an elevated SIH response in anticipation of social defeat when re-exposed to the social defeat environment. Taken together, our findings indicate that juvenile stress can induce long-term alterations in body temperature regulation and heighten the increase in temperature associated with anticipation of social defeat. The outcomes of behavioral measurements in these experiments, however, are severely affected by surgical stress. PMID:21557956

  6. Hydrogen sulfide regulates abiotic stress tolerance and biotic stress resistance in Arabidopsis.

    PubMed

    Shi, Haitao; Ye, Tiantian; Han, Ning; Bian, Hongwu; Liu, Xiaodong; Chan, Zhulong

    2015-07-01

    Hydrogen sulfide (H2S) is an important gaseous molecule in various plant developmental processes and plant stress responses. In this study, the transgenic Arabidopsis thaliana plants with modulated expressions of two cysteine desulfhydrases, and exogenous H2S donor (sodium hydrosulfide, NaHS) and H2S scavenger (hypotaurine, HT) pre-treated plants were used to dissect the involvement of H2S in plant stress responses. The cysteine desulfhydrases overexpressing plants and NaHS pre-treated plants exhibited higher endogenous H2S level and improved abiotic stress tolerance and biotic stress resistance, while cysteine desulfhydrases knockdown plants and HT pre-treated plants displayed lower endogenous H2S level and decreased stress resistance. Moreover, H2S upregulated the transcripts of multiple abiotic and biotic stress-related genes, and inhibited reactive oxygen species (ROS) accumulation. Interestingly, MIR393-mediated auxin signaling including MIR393a/b and their target genes (TIR1, AFB1, AFB2, and AFB3) was transcriptionally regulated by H2S, and was related with H2S-induced antibacterial resistance. Moreover, H2S regulated 50 carbon metabolites including amino acids, organic acids, sugars, sugar alcohols, and aromatic amines. Taken together, these results indicated that cysteine desulfhydrase and H2S conferred abiotic stress tolerance and biotic stress resistance, via affecting the stress-related gene expressions, ROS metabolism, metabolic homeostasis, and MIR393-targeted auxin receptors. PMID:25329496

  7. Molecular mechanisms of mTOR regulation by stress

    PubMed Central

    Heberle, Alexander Martin; Prentzell, Mirja Tamara; van Eunen, Karen; Bakker, Barbara Marleen; Grellscheid, Sushma Nagaraja; Thedieck, Kathrin

    2015-01-01

    Tumors are prime examples of cell growth in unfavorable environments that elicit cellular stress. The high metabolic demand and insufficient vascularization of tumors cause a deficiency of oxygen and nutrients. Oncogenic mutations map to signaling events via mammalian target of rapamycin (mTOR), metabolic pathways, and mitochondrial function. These alterations have been linked with cellular stresses, in particular endoplasmic reticulum (ER) stress, hypoxia, and oxidative stress. Yet tumors survive these challenges and acquire highly energy-demanding traits, such as overgrowth and invasiveness. In this review we focus on stresses that occur in cancer cells and discuss them in the context of mTOR signaling. Of note, many tumor traits require mTOR complex 1 (mTORC1) activity, but mTORC1 hyperactivation eventually sensitizes cells to apoptosis. Thus, mTORC1 activity needs to be balanced in cancer cells. We provide an overview of the mechanisms contributing to mTOR regulation by stress and suggest a model wherein stress granules function as guardians of mTORC1 signaling, allowing cancer cells to escape stress-induced cell death. PMID:27308421

  8. Stress Regulates Endocannabinoid-CB1 Receptor Signaling

    PubMed Central

    Hillard, Cecilia J.

    2014-01-01

    The CB1 cannabinoid receptor is a G protein coupled receptor that is widely expressed throughout the brain. The endogenous ligands for the CB1 receptor (endocannabinoids) are N-arachidonylethanolamine and 2-arachidonoylglycerol; together the endocannabinoids and CB1R subserve activity dependent, retrograde inhibition of neurotransmitter release in the brain. Deficiency of CB1 receptor signaling is associated with anhedonia, anxiety, and persistence of negative memories. CB1 receptor-endocannabinoid signaling is activated by stress and functions to buffer or dampen the behavioral and endocrine effects of acute stress. Its role in regulation of neuronal responses is more complex. Chronic variable stress exposure reduces endocannabinoid-CB1 receptor signaling and it is hypothesized that the resultant deficiency in endocannabinoid signaling contributes to the negative consequences of chronic stress. On the other hand, repeated exposure to the same stress can sensitize CB1 receptor signaling, resulting in dampening of the stress response. Data are reviewed that support the hypothesis that CB1 receptor signaling is stress responsive and that maintaining robust endocannabinoid/CB1 receptor signaling provides resilience against the development of stress-related pathologies. PMID:24882055

  9. Mutation as a Stress Response and the Regulation of Evolvability

    PubMed Central

    Galhardo, Rodrigo S.; Hastings, P. J.; Rosenberg, Susan M.

    2010-01-01

    Our concept of a stable genome is evolving to one in which genomes are plastic and responsive to environmental changes. Growing evidence shows that a variety of environmental stresses induce genomic instability in bacteria, yeast, and human cancer cells, generating occasional fitter mutants and potentially accelerating adaptive evolution. The emerging molecular mechanisms of stress-induced mutagenesis vary but share telling common components that underscore two common themes. The first is the regulation of mutagenesis in time by cellular stress responses, which promote random mutations specifically when cells are poorly adapted to their environments, i.e., when they are stressed. A second theme is the possible restriction of random mutagenesis in genomic space, achieved via coupling of mutation-generating machinery to local events such as DNA-break repair or transcription. Such localization may minimize accumulation of deleterious mutations in the genomes of rare fitter mutants, and promote local concerted evolution. Although mutagenesis induced by stresses other than direct damage to DNA was previously controversial, evidence for the existence of various stress-induced mutagenesis programs is now overwhelming and widespread. Such mechanisms probably fuel evolution of microbial pathogenesis and antibiotic-resistance, and tumor progression and chemotherapy resistance, all of which occur under stress, driven by mutations. The emerging commonalities in stress-induced-mutation mechanisms provide hope for new therapeutic interventions for all of these processes. PMID:17917874

  10. Characterization of the Hypothalamic-Pituitary-Adrenal-Axis in Familial Longevity under Resting Conditions

    PubMed Central

    Jansen, Steffy W.; Roelfsema, Ferdinand; Akintola, Abimbola A.; Oei, Nicole Y.; Cobbaert, Christa M.; Ballieux, Bart E.; van der Grond, Jeroen; Westendorp, Rudi G.; Pijl, Hanno; van Heemst, Diana

    2015-01-01

    Objective The hypothalamic-pituitary-adrenal (HPA)-axis is the most important neuro-endocrine stress response system of our body which is of critical importance for survival. Disturbances in HPA-axis activity have been associated with adverse metabolic and cognitive changes. Humans enriched for longevity have less metabolic and cognitive disturbances and therefore diminished activity of the HPA axis may be a potential candidate mechanism underlying healthy familial longevity. Here, we compared 24-h plasma ACTH and serum cortisol concentration profiles and different aspects of the regulation of the HPA-axis in offspring from long-lived siblings, who are enriched for familial longevity and age-matched controls. Design Case-control study within the Leiden Longevity study cohort consisting of 20 middle-aged offspring of nonagenarian siblings (offspring) together with 18 partners (controls). Methods During 24 h, venous blood was sampled every 10 minutes for determination of circulatory ACTH and cortisol concentrations. Deconvolution analysis, cross approximate entropy analysis and ACTH-cortisol-dose response modeling were used to assess, respectively, ACTH and cortisol secretion parameters, feedforward and feedback synchrony and adrenal gland ACTH responsivity. Results Mean (95% Confidence Interval) basal ACTH secretion was higher in male offspring compared to male controls (645 (324-1286) ngl/L/24 h versus 240 (120-477) ng/L/24 h, P = 0.05). Other ACTH and cortisol secretion parameters did not differ between offspring and controls. In addition, no significant differences in feedforward and feedback synchrony and adrenal gland ACTH responsivity were observed between groups. Conclusions These results suggest that familial longevity is not associated with major differences in HPA-axis activity under resting conditions, although modest, sex-specific differences may exist between groups that might be clinically relevant. PMID:26193655

  11. Chloroplast Retrograde Regulation of Heat Stress Responses in Plants.

    PubMed

    Sun, Ai-Zhen; Guo, Fang-Qing

    2016-01-01

    It is well known that intracellular signaling from chloroplast to nucleus plays a vital role in stress responses to survive environmental perturbations. The chloroplasts were proposed as sensors to heat stress since components of the photosynthetic apparatus housed in the chloroplast are the major targets of thermal damage in plants. Thus, communicating subcellular perturbations to the nucleus is critical during exposure to extreme environmental conditions such as heat stress. By coordinating expression of stress specific nuclear genes essential for adaptive responses to hostile environment, plants optimize different cell functions and activate acclimation responses through retrograde signaling pathways. The efficient communication between plastids and the nucleus is highly required for such diverse metabolic and biosynthetic functions during adaptation processes to environmental stresses. In recent years, several putative retrograde signals released from plastids that regulate nuclear genes have been identified and signaling pathways have been proposed. In this review, we provide an update on retrograde signals derived from tetrapyrroles, carotenoids, reactive oxygen species (ROS) and organellar gene expression (OGE) in the context of heat stress responses and address their roles in retrograde regulation of heat-responsive gene expression, systemic acquired acclimation, and cellular coordination in plants. PMID:27066042

  12. Chloroplast Retrograde Regulation of Heat Stress Responses in Plants

    PubMed Central

    Sun, Ai-Zhen; Guo, Fang-Qing

    2016-01-01

    It is well known that intracellular signaling from chloroplast to nucleus plays a vital role in stress responses to survive environmental perturbations. The chloroplasts were proposed as sensors to heat stress since components of the photosynthetic apparatus housed in the chloroplast are the major targets of thermal damage in plants. Thus, communicating subcellular perturbations to the nucleus is critical during exposure to extreme environmental conditions such as heat stress. By coordinating expression of stress specific nuclear genes essential for adaptive responses to hostile environment, plants optimize different cell functions and activate acclimation responses through retrograde signaling pathways. The efficient communication between plastids and the nucleus is highly required for such diverse metabolic and biosynthetic functions during adaptation processes to environmental stresses. In recent years, several putative retrograde signals released from plastids that regulate nuclear genes have been identified and signaling pathways have been proposed. In this review, we provide an update on retrograde signals derived from tetrapyrroles, carotenoids, reactive oxygen species (ROS) and organellar gene expression (OGE) in the context of heat stress responses and address their roles in retrograde regulation of heat-responsive gene expression, systemic acquired acclimation, and cellular coordination in plants. PMID:27066042

  13. Integrating metabolism and longevity through insulin and IGF1 signaling

    PubMed Central

    Sadagurski, Marianna; White, Morris F.

    2014-01-01

    Understanding how metabolism integrates nutrient homeostasis with life span is a complicated undertaking. The insulin pathway coordinates growth, development, metabolic homoeostasis, fertility and stress resistance, which ultimately influence lifespan. From a clinical perspective, compensatory hyperinsulinemia to overcome systemic insulin resistance is thought to be a healthy goal, because it circumvents to immediate catastrophic consequences of hyperglycemia; however, work in flies, nematodes and mice indicate that excess insulin signaling ultimately damages cellular function and accelerates aging. Maintenance of the central nervous system (CNS) has particular importance for lifespan. Depending upon the exact site, reduced insulin/IGF1 signaling in the CNS can dysregulate peripheral energy homeostasis and metabolism, promote obesity, and extend lifespan. In this review, we explore how genetic manipulations of insulin/IGF1 signaling components are beginning to reveal neuronal circuits which might resolve the central regulation of systemic metabolism from organism longevity. PMID:23391244

  14. Molecular links between cellular senescence, longevity and age-related diseases - a systems biology perspective.

    PubMed

    Tacutu, Robi; Budovsky, Arie; Yanai, Hagai; Fraifeld, Vadim E

    2011-12-01

    The role of cellular senescence (CS) in age-related diseases (ARDs) is a quickly emerging topic in aging research. Our comprehensive data mining revealed over 250 genes tightly associated with CS. Using systems biology tools, we found that CS is closely interconnected with aging, longevity and ARDs, either by sharing common genes and regulators or by protein-protein interactions and eventually by common signaling pathways. The most enriched pathways across CS, ARDs and aging-associated conditions (oxidative stress and chronic inflammation) are growth-promoting pathways and the pathways responsible for cell-extracellular matrix interactions and stress response. Of note, the patterns of evolutionary conservation of CS and cancer genes showed a high degree of similarity, suggesting the co-evolution of these two phenomena. Moreover, cancer genes and microRNAs seem to stand at the crossroad between CS and ARDs. Our analysis also provides the basis for new predictions: the genes common to both cancer and other ARD(s) are highly likely candidates to be involved in CS and vice versa. Altogether, this study shows that there are multiple links between CS, aging, longevity and ARDs, suggesting a common molecular basis for all these conditions. Modulating CS may represent a potential pro-longevity and anti-ARDs therapeutic strategy. PMID:22184282

  15. WRKY Transcription Factors: Molecular Regulation and Stress Responses in Plants

    PubMed Central

    Phukan, Ujjal J.; Jeena, Gajendra S.; Shukla, Rakesh K.

    2016-01-01

    Plants in their natural habitat have to face multiple stresses simultaneously. Evolutionary adaptation of developmental, physiological, and biochemical parameters give advantage over a single window of stress but not multiple. On the other hand transcription factors like WRKY can regulate diverse responses through a complicated network of genes. So molecular orchestration of WRKYs in plant may provide the most anticipated outcome of simultaneous multiple responses. Activation or repression through W-box and W-box like sequences is regulated at transcriptional, translational, and domain level. Because of the tight regulation involved in specific recognition and binding of WRKYs to downstream promoters, they have become promising candidate for crop improvement. Epigenetic, retrograde and proteasome mediated regulation enable WRKYs to attain the dynamic cellular homeostatic reprograming. Overexpression of several WRKYs face the paradox of having several beneficial affects but with some unwanted traits. These overexpression-associated undesirable phenotypes need to be identified and removed for proper growth, development and yeild. Taken together, we have highlighted the diverse regulation and multiple stress response of WRKYs in plants along with the future prospects in this field of research. PMID:27375634

  16. Pneumococcal Hydrogen Peroxide–Induced Stress Signaling Regulates Inflammatory Genes

    PubMed Central

    Loose, Maria; Hudel, Martina; Zimmer, Klaus-Peter; Garcia, Ernesto; Hammerschmidt, Sven; Lucas, Rudolf; Chakraborty, Trinad; Pillich, Helena

    2015-01-01

    Microbial infections can induce aberrant responses in cellular stress pathways, leading to translational attenuation, metabolic restriction, and activation of oxidative stress, with detrimental effects on cell survival. Here we show that infection of human airway epithelial cells with Streptococcus pneumoniae leads to induction of endoplasmic reticulum (ER) and oxidative stress, activation of mitogen-associated protein kinase (MAPK) signaling pathways, and regulation of their respective target genes. We identify pneumococcal H2O2 as the causative agent for these responses, as both catalase-treated and pyruvate oxidase-deficient bacteria lacked these activities. Pneumococcal H2O2 induced nuclear NF-κB translocation and transcription of proinflammatory cytokines. Inhibition of translational arrest and ER stress by salubrinal or of MAPK signaling pathways attenuate cytokine transcription. These results provide strong evidence for the notion that inhibition of translation is an important host pathway in monitoring harmful pathogen-associated activities, thereby enabling differentiation between pathogenic and nonpathogenic bacteria. PMID:25183769

  17. Proteomic analysis of rice leaves shows the different regulations to osmotic stress and stress signals.

    PubMed

    Shu, Lie-Bo; Ding, Wei; Wu, Jin-Hong; Feng, Fang-Jun; Luo, Li-Jun; Mei, Han-Wei

    2010-11-01

    Following the idea of partial root-zone drying (PRD) in crop cultivation, the morphological and physiological responses to partial root osmotic stress (PROS) and whole root osmotic stress (WROS) were investigated in rice. WROS caused stress symptoms like leaf rolling and membrane leakage. PROS stimulated stress signals, but did not cause severe leaf damage. By proteomic analysis, a total of 58 proteins showed differential expression after one or both treatments, and functional classification of these proteins suggests that stress signals regulate photosynthesis, carbohydrate and energy metabolism. Two other proteins (anthranilate synthase and submergence-induced nickel-binding protein) were upregulated only in the PROS plants, indicating their important roles in stress resistance. Additionally, more enzymes were involved in stress defense, redox homeostasis, lignin and ethylene synthesis in WROS leaves, suggesting a more comprehensive regulatory mechanism induced by osmotic stress. This study provides new insights into the complex molecular networks within plant leaves involved in the adaptation to osmotic stress and stress signals. PMID:20977656

  18. Regulation of Photosynthesis during Abiotic Stress-Induced Photoinhibition.

    PubMed

    Gururani, Mayank Anand; Venkatesh, Jelli; Tran, Lam Son Phan

    2015-09-01

    Plants as sessile organisms are continuously exposed to abiotic stress conditions that impose numerous detrimental effects and cause tremendous loss of yield. Abiotic stresses, including high sunlight, confer serious damage on the photosynthetic machinery of plants. Photosystem II (PSII) is one of the most susceptible components of the photosynthetic machinery that bears the brunt of abiotic stress. In addition to the generation of reactive oxygen species (ROS) by abiotic stress, ROS can also result from the absorption of excessive sunlight by the light-harvesting complex. ROS can damage the photosynthetic apparatus, particularly PSII, resulting in photoinhibition due to an imbalance in the photosynthetic redox signaling pathways and the inhibition of PSII repair. Designing plants with improved abiotic stress tolerance will require a comprehensive understanding of ROS signaling and the regulatory functions of various components, including protein kinases, transcription factors, and phytohormones, in the responses of photosynthetic machinery to abiotic stress. Bioenergetics approaches, such as chlorophyll a transient kinetics analysis, have facilitated our understanding of plant vitality and the assessment of PSII efficiency under adverse environmental conditions. This review discusses the current understanding and indicates potential areas of further studies on the regulation of the photosynthetic machinery under abiotic stress. PMID:25997389

  19. Proteolytic regulation of stress response pathways in Escherichia coli.

    PubMed

    Micevski, Dimce; Dougan, David A

    2013-01-01

    Maintaining correct cellular function is a fundamental biological process for all forms of life. A critical aspect of this process is the maintenance of protein homeostasis (proteostasis) in the cell, which is largely performed by a group of proteins, referred to as the protein quality control (PQC) network. This network of proteins, comprised of chaperones and proteases, is critical for maintaining proteostasis not only during favourable growth conditions, but also in response to stress. Indeed proteases play a crucial role in the clearance of unwanted proteins that accumulate during stress, but more importantly, in the activation of various different stress response pathways. In bacteria, the cells response to stress is usually orchestrated by a specific transcription factor (sigma factor). In Escherichia coli there are seven different sigma factors, each of which responds to a particular stress, resulting in the rapid expression of a specific set of genes. The cellular concentration of each transcription factor is tightly controlled, at the level of transcription, translation and protein stability. Here we will focus on the proteolytic regulation of two sigma factors (σ(32) and σ(S)), which control the heat and general stress response pathways, respectively. This review will also briefly discuss the role proteolytic systems play in the clearance of unwanted proteins that accumulate during stress. PMID:23479439

  20. A quiescent path to plant longevity.

    PubMed

    Heyman, Jefri; Kumpf, Robert P; De Veylder, Lieven

    2014-08-01

    The giant sequoia and the bristlecone pine trees are capable of living up to several hundreds or even thousands of years. Plants achieve this longevity by regenerating stem cells capable of giving rise to all differentiated cells. Plant stem cells reside in specific niches with high mitotic activity that are known as meristems. Remarkably, at the center of the root stem cell niche (SCN) resides a group of mitotically inactive cells known as the quiescent center (QC). Recent studies suggest that stress-related phytohormones and DNA damage can initiate QC cell division, resulting in the replenishment of stem cells surrounding the QC. We therefore propose that the QC represents a pool of backup cells that serve to replace damaged stem cells, thereby contributing to plant longevity. PMID:24704103

  1. Ezrin Inhibition Up-regulates Stress Response Gene Expression.

    PubMed

    Çelik, Haydar; Bulut, Gülay; Han, Jenny; Graham, Garrett T; Minas, Tsion Z; Conn, Erin J; Hong, Sung-Hyeok; Pauly, Gary T; Hayran, Mutlu; Li, Xin; Özdemirli, Metin; Ayhan, Ayşe; Rudek, Michelle A; Toretsky, Jeffrey A; Üren, Aykut

    2016-06-17

    Ezrin is a member of the ERM (ezrin/radixin/moesin) family of proteins that links cortical cytoskeleton to the plasma membrane. High expression of ezrin correlates with poor prognosis and metastasis in osteosarcoma. In this study, to uncover specific cellular responses evoked by ezrin inhibition that can be used as a specific pharmacodynamic marker(s), we profiled global gene expression in osteosarcoma cells after treatment with small molecule ezrin inhibitors, NSC305787 and NSC668394. We identified and validated several up-regulated integrated stress response genes including PTGS2, ATF3, DDIT3, DDIT4, TRIB3, and ATF4 as novel ezrin-regulated transcripts. Analysis of transcriptional response in skin and peripheral blood mononuclear cells from NSC305787-treated mice compared with a control group revealed that, among those genes, the stress gene DDIT4/REDD1 may be used as a surrogate pharmacodynamic marker of ezrin inhibitor compound activity. In addition, we validated the anti-metastatic effects of NSC305787 in reducing the incidence of lung metastasis in a genetically engineered mouse model of osteosarcoma and evaluated the pharmacokinetics of NSC305787 and NSC668394 in mice. In conclusion, our findings suggest that cytoplasmic ezrin, previously considered a dormant and inactive protein, has important functions in regulating gene expression that may result in down-regulation of stress response genes. PMID:27137931

  2. Effects of perinatal stress and maternal traumatic stress on the cortisol regulation of preterm infants.

    PubMed

    Habersaat, Stephanie; Borghini, Ayala; Nessi, Jennifer; Forcada-Guex, Margarita; Müller-Nix, Carole; Pierrehumbert, Blaise; Ansermet, François

    2014-08-01

    Preterm infants experience intense stress during the perinatal period because they endure painful and intense medical procedures. Repeated activation of the hypothalamic-pituitary-adrenal (HPA) axis during this period may have long-term effects on subsequent cortisol regulation. A premature delivery may also be intensely stressful for the parents, and they may develop symptoms of posttraumatic stress disorder (PTSD). Usable saliva samples were collected (4 times per day over 2 days, in the morning at awakening, at midday, in the afternoon, and in the evening before going to bed) to assess the diurnal cortisol regulation from 46 preterm infants when the infants were 12 months of corrected age (∼ 14 months after birth). Mothers reported their level of PTSD symptoms. The results showed an interaction between perinatal stress and maternal traumatic stress on the diurnal cortisol slope of preterm infants (R(2) = .32). This suggests that the HPA axis of preterm infants exposed to high perinatal stress may be more sensitive to subsequent environmental stress. PMID:25158643

  3. Exercise and longevity.

    PubMed

    Gremeaux, Vincent; Gayda, Mathieu; Lepers, Romuald; Sosner, Philippe; Juneau, Martin; Nigam, Anil

    2012-12-01

    Aging is a natural and complex physiological process influenced by many factors, some of which are modifiable. As the number of older individuals continues to increase, it is important to develop interventions that can be easily implemented and contribute to "successful aging". In addition to a healthy diet and psychosocial well-being, the benefits of regular exercise on mortality, and the prevention and control of chronic disease affecting both life expectancy and quality of life are well established. We summarize the benefits of regular exercise on longevity, present the current knowledge regarding potential mechanisms, and outline the main recommendations. Exercise can partially reverse the effects of the aging process on physiological functions and preserve functional reserve in the elderly. Numerous studies have shown that maintaining a minimum quantity and quality of exercise decreases the risk of death, prevents the development of certain cancers, lowers the risk of osteoporosis and increases longevity. Training programs should include exercises aimed at improving cardiorespiratory fitness and muscle function, as well as flexibility and balance. Though the benefits of physical activity appear to be directly linked to the notion of training volume and intensity, further research is required in the elderly, in order to develop more precise recommendations, bearing in mind that the main aim is to foster long-term adherence to physical activity in this growing population. PMID:23063021

  4. TRIB2 regulates normal and stress-induced thymocyte proliferation

    PubMed Central

    Liang, Kai Ling; O’Connor, Caitriona; Veiga, J Pedro; McCarthy, Tommie V; Keeshan, Karen

    2016-01-01

    TRIB2, a serine/threonine pseudokinase identified as an oncogene, is expressed at high levels in the T-cell compartment of hematopoiesis. The proliferation of developing thymocytes is tightly controlled to prevent leukemic transformation of T cells. Here we examine Trib2 loss in murine hematopoiesis under steady state and proliferative stress conditions, including genotoxic and oncogenic stress. Trib2−/− developing thymocytes show increased proliferation, and Trib2−/− mice have significantly higher thymic cellularity at steady state. During stress hematopoiesis, Trib2−/− developing thymocytes undergo accelerated proliferation and demonstrate hypersensitivity to 5-fluorouracil (5-FU)-induced cell death. Despite the increased cell death post 5-FU-induced proliferative stress, Trib2−/− mice exhibit accelerated thymopoietic recovery post treatment due to increased cell division kinetics of developing thymocytes. The increased proliferation in Trib2−/− thymocytes was exacerbated under oncogenic stress. In an experimental murine T-cell acute lymphoblastic leukemia (T-ALL) model, Trib2−/− mice had reduced latency in vivo, which associated with impaired MAP kinase (MAPK) activation. High and low expression levels of Trib2 correlate with immature and mature subtypes of human T-ALL, respectively, and associate with MAPK. Thus, TRIB2 emerges as a novel regulator of thymocyte cellular proliferation, important for the thymopoietic response to genotoxic and oncogenic stress, and possessing tumor suppressor function. PMID:27462446

  5. Extracellular signal-regulated kinase-2 within the ventral tegmental area regulates responses to stress.

    PubMed

    Iñiguez, Sergio D; Vialou, Vincent; Warren, Brandon L; Cao, Jun-Li; Alcantara, Lyonna F; Davis, Lindsey C; Manojlovic, Zarko; Neve, Rachael L; Russo, Scott J; Han, Ming-Hu; Nestler, Eric J; Bolaños-Guzmán, Carlos A

    2010-06-01

    Neurotrophic factors and their signaling pathways have been implicated in the neurobiological adaptations in response to stress and the regulation of mood-related behaviors. A candidate signaling molecule implicated in mediating these cellular responses is the extracellular signal-regulated kinase (ERK1/2), although its functional role in mood regulation remains to be fully elucidated. Here we show that acute (1 d) or chronic (4 weeks) exposure to unpredictable stress increases phosphorylation of ERK1/2 and of two downstream targets (ribosomal S6 kinase and mitogen- and stress-activated protein kinase 1) within the ventral tegmental area (VTA), an important substrate for motivated behavior and mood regulation. Using herpes simplex virus-mediated gene transfer to assess the functional significance of this ERK induction, we show that overexpressing ERK2 within the VTA increases susceptibility to stress as measured in the forced swim test, responses to unconditioned nociceptive stimuli, and elevated plus maze in Sprague Dawley male rats, and in the tail suspension test and chronic social defeat stress procedure in C57BL/6 male mice. In contrast, blocking ERK2 activity in the VTA produces stress-resistant behavioral responses in these same assays and also blocks a chronic stress-induced reduction in sucrose preference. The effects induced by ERK2 blockade were accompanied by decreases in the firing frequency of VTA dopamine neurons, an important electrophysiological hallmark of resilient-like behavior. Together, these results strongly implicate a role for ERK2 signaling in the VTA as a key modulator of responsiveness to stress and mood-related behaviors. PMID:20519540

  6. Familial Risk for Exceptional Longevity

    PubMed Central

    Sebastiani, Paola; Andersen, Stacy L.; McIntosh, Avery I.; Nussbaum, Lisa; Stevenson, Meredith D.; Pierce, Leslie; Xia, Samantha; Salance, Kelly; Perls, Thomas T.

    2015-01-01

    One of the most glaring deficiencies in the current assessment of mortality risk is the lack of information concerning the impact of familial longevity. In this work, we update estimates of sibling relative risk of living to extreme ages using data from more than 1,700 sibships, and we begin to examine the trend for heritability for different birth-year cohorts. We also build a network model that can be used to compute the increased chance for exceptional longevity of a subject, conditional on his family history of longevity. The network includes familial longevity from three generations and can be used to understand the effects of paternal and maternal longevity on an individual's chance to live to an extreme age. PMID:27041978

  7. Regulation of myokine expression: Role of exercise and cellular stress.

    PubMed

    Ost, Mario; Coleman, Verena; Kasch, Juliane; Klaus, Susanne

    2016-09-01

    Exercise training is well known to improve physical fitness and to combat chronic diseases and aging related disorders. Part of this is thought to be mediated by myokines, muscle derived secretory proteins (mainly cytokines) that elicit auto/paracrine but also endocrine effects on organs such as liver, adipose tissue, and bone. Today, several hundred potential myokines have been identified most of them not exclusive to muscle cells. Strenuous exercise is associated with increased production of free radicals and reactive oxidant species (ROS) as well as endoplasmic reticulum (ER)-stress which at an excessive level can lead to muscle damage and cell death. On the other hand, transient elevations in oxidative and ER-stress are thought to be necessary for adaptive improvements by regular exercise through a hormesis action termed mitohormesis since mitochondria are essential for the generation of energy and tightly connected to ER- and oxidative stress. Exercise induced myokines have been identified by various in vivo and in vitro approaches and accumulating evidence suggests that ROS and ER-stress linked pathways are involved in myokine induction. For example, interleukin (IL)-6, the prototypic exercise myokine is also induced by oxidative and ER-stress. Exercise induced expression of some myokines such as irisin and meteorin-like is linked to the transcription factor PGC-1α and apparently not related to ER-stress whereas typical ER-stress induced cytokines such as FGF-21 and GDF-15 are not exercise myokines under normal physiological conditions. Recent technological advances have led to the identification of numerous potential new myokines but for most of them regulation by oxidative and ER-stress still needs to be unraveled. PMID:26898145

  8. Quorum sensing regulates the osmotic stress response in Vibrio harveyi.

    PubMed

    van Kessel, Julia C; Rutherford, Steven T; Cong, Jian-Ping; Quinodoz, Sofia; Healy, James; Bassler, Bonnie L

    2015-01-01

    Bacteria use a chemical communication process called quorum sensing to monitor cell density and to alter behavior in response to fluctuations in population numbers. Previous studies with Vibrio harveyi have shown that LuxR, the master quorum-sensing regulator, activates and represses >600 genes. These include six genes that encode homologs of the Escherichia coli Bet and ProU systems for synthesis and transport, respectively, of glycine betaine, an osmoprotectant used during osmotic stress. Here we show that LuxR activates expression of the glycine betaine operon betIBA-proXWV, which enhances growth recovery under osmotic stress conditions. BetI, an autorepressor of the V. harveyi betIBA-proXWV operon, activates the expression of genes encoding regulatory small RNAs that control quorum-sensing transitions. Connecting quorum-sensing and glycine betaine pathways presumably enables V. harveyi to tune its execution of collective behaviors to its tolerance to stress. PMID:25313392

  9. Quorum Sensing Regulates the Osmotic Stress Response in Vibrio harveyi

    PubMed Central

    Rutherford, Steven T.; Cong, Jian-Ping; Quinodoz, Sofia; Healy, James

    2014-01-01

    Bacteria use a chemical communication process called quorum sensing to monitor cell density and to alter behavior in response to fluctuations in population numbers. Previous studies with Vibrio harveyi have shown that LuxR, the master quorum-sensing regulator, activates and represses >600 genes. These include six genes that encode homologs of the Escherichia coli Bet and ProU systems for synthesis and transport, respectively, of glycine betaine, an osmoprotectant used during osmotic stress. Here we show that LuxR activates expression of the glycine betaine operon betIBA-proXWV, which enhances growth recovery under osmotic stress conditions. BetI, an autorepressor of the V. harveyi betIBA-proXWV operon, activates the expression of genes encoding regulatory small RNAs that control quorum-sensing transitions. Connecting quorum-sensing and glycine betaine pathways presumably enables V. harveyi to tune its execution of collective behaviors to its tolerance to stress. PMID:25313392

  10. ENaC regulation by proteases and shear stress

    PubMed Central

    Shi, Shujie; Carattino, Marcelo D.; Hughey, Rebecca P.; Kleyman, Thomas R.

    2013-01-01

    Epithelial Na+ channels (ENaCs) are comprised of subunits that have large extracellular regions linked to membrane spanning domains where the channel pore and gate reside. A variety of external factors modify channel activity by interacting at sites within extracellular regions that lead to conformational changes that are transmitted to the channel gate and alter channel open probability. Our review addresses two external factors that have important roles in regulating channel activity, proteases and laminar shear stress. PMID:23547932

  11. Epigenetic Regulation of Oxidative Stress in Ischemic Stroke

    PubMed Central

    Zhao, Haiping; Han, Ziping; Ji, Xunming; Luo, Yumin

    2016-01-01

    The prevalence and incidence of stroke rises with life expectancy. However, except for the use of recombinant tissue-type plasminogen activator, the translation of new therapies for acute stroke from animal models into humans has been relatively unsuccessful. Oxidative DNA and protein damage following stroke is typically associated with cell death. Cause-effect relationships between reactive oxygen species and epigenetic modifications have been established in aging, cancer, acute pancreatitis, and fatty liver disease. In addition, epigenetic regulatory mechanisms during stroke recovery have been reviewed, with focuses mainly on neural apoptosis, necrosis, and neuroplasticity. However, oxidative stress-induced epigenetic regulation in vascular neural networks following stroke has not been sufficiently explored. Improved understanding of the epigenetic regulatory network upon oxidative stress may provide effective antioxidant approaches for treating stroke. In this review, we summarize the epigenetic events, including DNA methylation, histone modification, and microRNAs, that result from oxidative stress following experimental stroke in animal and cell models, and the ways in which epigenetic changes and their crosstalk influence the redox state in neurons, glia, and vascular endothelial cells, helping us to understand the foregone and vicious epigenetic regulation of oxidative stress in the vascular neural network following stroke. PMID:27330844

  12. Gene regulation during cold stress acclimation in plants.

    PubMed

    Chinnusamy, Viswanathan; Zhu, Jian-Kang; Sunkar, Ramanjulu

    2010-01-01

    Cold stress adversely affects plant growth and development and thus limits crop productivity. Diverse plant species tolerate cold stress to a varying degree, which depends on reprogramming gene expression to modify their physiology, metabolism, and growth. Cold signal in plants is transmitted to activate CBF-dependent (C-repeat/drought-responsive element binding factor-dependent) and CBF-independent transcriptional pathway, of which CBF-dependent pathway activates CBF regulon. CBF transcription factor genes are induced by the constitutively expressed ICE1 (inducer of CBF expression 1) by binding to the CBF promoter. ICE1-CBF cold response pathway is conserved in diverse plant species. Transgenic analysis in different plant species revealed that cold tolerance can be significantly enhanced by genetic engineering CBF pathway. Posttranscriptional regulation at pre-mRNA processing and export from nucleus plays a role in cold acclimation. Small noncoding RNAs, namely micro-RNAs (miRNAs) and small interfering RNAs (siRNAs), are emerging as key players of posttranscriptional gene silencing. Cold stress-regulated miRNAs have been identified in Arabidopsis and rice. In this chapter, recent advances on cold stress signaling and tolerance are highlighted. PMID:20387039

  13. Whole gene family expression and drought stress regulation of aquaporins.

    PubMed

    Alexandersson, Erik; Fraysse, Laure; Sjövall-Larsen, Sara; Gustavsson, Sofia; Fellert, Maria; Karlsson, Maria; Johanson, Urban; Kjellbom, Per

    2005-10-01

    Since many aquaporins (AQPs) act as water channels, they are thought to play an important role in plant water relations. It is therefore of interest to study the expression patterns of AQP isoforms in order to further elucidate their involvement in plant water transport. We have monitored the expression patterns of all 35 Arabidopsis AQPs in leaves, roots and flowers by cDNA microarrays, specially designed for AQPs, and by quantitative real-time reverse transcriptase PCR (Q-RT-PCR). This showed that many AQPs are pre-dominantly expressed in either root or flower organs, whereas no AQP isoform seem to be leaf specific. Looking at the AQP subfamilies, most plasma membrane intrinsic proteins (PIPs) and some tonoplast intrinsic proteins (TIPs) have a high level of expression, while NOD26-like proteins (NIPs) are present at a much lower level. In addition, we show that PIP transcripts are generally down-regulated upon gradual drought stress in leaves, with the exception of AtPIP1;4 and AtPIP2;5, which are up-regulated. AtPIP2;6 and AtSIP1;1 are constitutively expressed and not significantly affected by the drought stress. The transcriptional down-regulation of PIP genes upon drought stress could also be observed on the protein level. PMID:16235111

  14. MOF maintains transcriptional programs regulating cellular stress response

    PubMed Central

    Sheikh, B N; Bechtel-Walz, W; Lucci, J; Karpiuk, O; Hild, I; Hartleben, B; Vornweg, J; Helmstädter, M; Sahyoun, A H; Bhardwaj, V; Stehle, T; Diehl, S; Kretz, O; Voss, A K; Thomas, T; Manke, T; Huber, T B; Akhtar, A

    2016-01-01

    MOF (MYST1, KAT8) is the major H4K16 lysine acetyltransferase (KAT) in Drosophila and mammals and is essential for embryonic development. However, little is known regarding the role of MOF in specific cell lineages. Here we analyze the differential role of MOF in proliferating and terminally differentiated tissues at steady state and under stress conditions. In proliferating cells, MOF directly binds and maintains the expression of genes required for cell cycle progression. In contrast, MOF is dispensable for terminally differentiated, postmitotic glomerular podocytes under physiological conditions. However, in response to injury, MOF is absolutely critical for podocyte maintenance in vivo. Consistently, we detect defective nuclear, endoplasmic reticulum and Golgi structures, as well as presence of multivesicular bodies in vivo in podocytes lacking Mof following injury. Undertaking genome-wide expression analysis of podocytes, we uncover several MOF-regulated pathways required for stress response. We find that MOF, along with the members of the non-specific lethal but not the male-specific lethal complex, directly binds to genes encoding the lysosome, endocytosis and vacuole pathways, which are known regulators of podocyte maintenance. Thus, our work identifies MOF as a key regulator of cellular stress response in glomerular podocytes. PMID:26387537

  15. Negative Emotion Regulation in Patients with Posttraumatic Stress Disorder

    PubMed Central

    Qiu, Mingguo; Zhang, Jingna; Sang, Linqiong; Wang, Li; Xie, Bing; Wang, Jian; Li, Min

    2013-01-01

    Objective To explore the neural mechanisms of negative emotion regulation in patients with post-traumatic stress disorder (PTSD). Methods Twenty PTSD patients and 20 healthy subjects were recruited. Event-related functional magnetic resonance imaging (fMRI) was used to investigate the modification of emotional responses to negative stimuli. Participants were required to regulate their emotional reactions according to the auditory regulation instructions via headphones, to maintain, enhance or diminish responses to negative stimuli during fMRI scans. Results The PTSD group showed poorer modification performance than the control group when diminishing responses to negative stimuli. On fMRI, the PTSD group showed decreased activation in the inferior frontal cortex, inferior parietal lobule, insula and putamen, and increased activation in posterior cingulate cortex and amygdala during up-regulation of negative emotion. Similar decreased activation regions were found during down-regulation of negative emotion, but no increased activation was found. Conclusion Trauma exposure might impair the ability to down-regulate negative emotion. The present findings will improve our understanding of the neural mechanisms of emotion regulation underlying PTSD. PMID:24349161

  16. Metabotropic GABA signalling modulates longevity in C. elegans

    PubMed Central

    Chun, Lei; Gong, Jianke; Yuan, Fengling; Zhang, Bi; Liu, Hongkang; Zheng, Tianlin; Yu, Teng; Xu, X. Z. Shawn; Liu, Jianfeng

    2015-01-01

    The nervous system plays an important but poorly understood role in modulating longevity. GABA, a prominent inhibitory neurotransmitter, is best known to regulate nervous system function and behaviour in diverse organisms. Whether GABA signalling affects aging, however, has not been explored. Here we examined mutants lacking each of the major neurotransmitters in C. elegans, and find that deficiency in GABA signalling extends lifespan. This pro-longevity effect is mediated by the metabotropic GABAB receptor GBB-1, but not ionotropic GABAA receptors. GBB-1 regulates lifespan through G protein-PLCβ signalling, which transmits longevity signals to the transcription factor DAF-16/FOXO, a key regulator of lifespan. Mammalian GABAB receptors can functionally substitute for GBB-1 in lifespan control in C. elegans. Our results uncover a new role of GABA signalling in lifespan regulation in C. elegans, raising the possibility that a similar process may occur in other organisms. PMID:26537867

  17. Oxidative Stress-Mediated Regulation of Proteasome Complexes*

    PubMed Central

    Aiken, Charity T.; Kaake, Robyn M.; Wang, Xiaorong; Huang, Lan

    2011-01-01

    Oxidative stress has been implicated in aging and many human diseases, notably neurodegenerative disorders and various cancers. The reactive oxygen species that are generated by aerobic metabolism and environmental stressors can chemically modify proteins and alter their biological functions. Cells possess protein repair pathways to rescue oxidized proteins and restore their functions. If these repair processes fail, oxidized proteins may become cytotoxic. Cell homeostasis and viability are therefore dependent on the removal of oxidatively damaged proteins. Numerous studies have demonstrated that the proteasome plays a pivotal role in the selective recognition and degradation of oxidized proteins. Despite extensive research, oxidative stress-triggered regulation of proteasome complexes remains poorly defined. Better understanding of molecular mechanisms underlying proteasome function in response to oxidative stress will provide a basis for developing new strategies aimed at improving cell viability and recovery as well as attenuating oxidation-induced cytotoxicity associated with aging and disease. Here we highlight recent advances in the understanding of proteasome structure and function during oxidative stress and describe how cells cope with oxidative stress through proteasome-dependent degradation pathways. PMID:21543789

  18. Endoplasmic reticulum stress regulation in hematopoietic stem cells.

    PubMed

    Miharada, Kenichi

    2016-08-01

    Adult hematopoietic stem cells (HSCs) reside in bone marrow and are maintained in a dormant state within a special microenvironment, their so-called "niche". Detaching from the niche induces cell cycle progression, resulting in a reduction of the reconstitution capacity of HSCs. In contrast, fetal liver HSCs actively divide without losing their stem cell potentials. Thus, it has been unclear what types of cellular responses and metabolic changes occur in growing HSCs. We previously discovered that HSCs express relatively low levels of endoplasmic reticulum (ER) chaperone proteins governing protein folding, making HSCs vulnerable to an elevation of stress signals caused by accumulation of un-/misfolded proteins (ER stress) upon in vitro culture. Interestingly, fetal liver HSCs do not show ER stress elevation despite unchanged levels of chaperone proteins. Our latest studies utilizing multiple mouse models revealed that in the fetal liver bile acids as chemical chaperones play a key role supporting the protein folding which results in the suppression of ER stress induction. These findings highlight the importance of ER stress regulations in hematopoiesis. PMID:27599423

  19. LTR retrotransposons, handy hitchhikers of plant regulation and stress response.

    PubMed

    Grandbastien, Marie-Angèle

    2015-04-01

    LTR retrotransposons are major components of plant genomes. They are regulated by a diverse array of external stresses and tissue culture conditions, displaying finely tuned responses to these stimuli, mostly in the form of upregulation. Second to stress conditions and tissue culture, meristems are also permissive for LTR retrotransposon expression, suggesting that a dedifferentiated cell status may represent a frequent activating condition. LTR regions are highly plastic and contain regulatory motifs similar to those of cellular genes. The activation of LTR retrotransposons results from interplay between the release of epigenetic silencing and the recruitment by LTRs of specific regulatory factors. Despite the role of LTR retrotransposons in driving plant genome diversification, convincing evidence for major mobilizations of LTR retrotransposons remains much rarer than observations of massive bursts of transcriptional upregulation. Current evidence suggests that LTR retrotransposon expression may be involved in host functional plasticity, acting as dispersed regulatory modules able to redirect stress stimuli to adjacent plant genes. This may be of crucial importance for plants that cannot escape stress, and have evolved complex and highly coordinated responses to external challenges. This article is part of a Special Issue entitled: Stress as a fundamental theme in cell plasticity. PMID:25086340

  20. Folliculin Regulates Ampk-Dependent Autophagy and Metabolic Stress Survival

    PubMed Central

    Nouët, Yann; Yan, Ming; Gingras, Marie-Claude; Schmeisser, Kathrin; Panaite, Lorena; Dupuy, Fanny; Kharitidi, Dmitri; Chotard, Laëtitia; Jones, Russell G.; Hall, David H.; Pause, Arnim

    2014-01-01

    Dysregulation of AMPK signaling has been implicated in many human diseases, which emphasizes the importance of characterizing AMPK regulators. The tumor suppressor FLCN, responsible for the Birt-Hogg Dubé renal neoplasia syndrome (BHD), is an AMPK-binding partner but the genetic and functional links between FLCN and AMPK have not been established. Strikingly, the majority of naturally occurring FLCN mutations predisposing to BHD are predicted to produce truncated proteins unable to bind AMPK, pointing to the critical role of this interaction in the tumor suppression mechanism. Here, we demonstrate that FLCN is an evolutionarily conserved negative regulator of AMPK. Using Caenorhabditis elegans and mammalian cells, we show that loss of FLCN results in constitutive activation of AMPK which induces autophagy, inhibits apoptosis, improves cellular bioenergetics, and confers resistance to energy-depleting stresses including oxidative stress, heat, anoxia, and serum deprivation. We further show that AMPK activation conferred by FLCN loss is independent of the cellular energy state suggesting that FLCN controls the AMPK energy sensing ability. Together, our data suggest that FLCN is an evolutionarily conserved regulator of AMPK signaling that may act as a tumor suppressor by negatively regulating AMPK function. PMID:24763318

  1. Homer2 regulates alcohol and stress cross-sensitization.

    PubMed

    Quadir, Sema G; Santos, Jaqueline Rocha Borges Dos; Campbell, Rianne R; Wroten, Melissa G; Singh, Nimrita; Holloway, John J; Bal, Sukhmani K; Camarini, Rosana; Szumlinski, Karen K

    2016-05-01

    An interaction exists between stress and alcohol in the etiology and chronicity of alcohol use disorders, yet a knowledge gap exists regarding the neurobiological underpinnings of this interaction. In this regard, we employed an 11-day unpredictable, chronic, mild stress (UCMS) procedure to examine for stress-alcohol cross-sensitization of motor activity as well as alcohol consumption/preference and intoxication. We also employed immunoblotting to relate the expression of glutamate receptor-related proteins within subregions of the nucleus accumbens (NAC) to the manifestation of behavioral cross-sensitization. UCMS mice exhibited a greater locomotor response to an acute injection of 2 g/kg alcohol than unstressed controls and this cross-sensitization extended to alcohol intake (0-20 percent), as well as to the intoxicating and sedative properties of 3 and 5 g/kg alcohol, respectively. Regardless of prior alcohol injection (2 g/kg), UCMS mice exhibited elevated NAC shell levels of mGlu1α, GluN2b and Homer2, as well as lower phospholipase Cβ within this subregion. GluN2b levels were also lower within the NAC core of UCMS mice. The expression of stress-alcohol locomotor cross-sensitization was associated with lower mGlu1α within the NAC core and lower extracellular signal-regulated kinase activity within both NAC subregions. As Homer2 regulates alcohol sensitization, we assayed also for locomotor cross-sensitization in Homer2 wild-type (WT) and knock-out (KO) mice. WT mice exhibited a very robust cross-sensitization that was absent in KO animals. These results indicate that a history of mild stress renders an animal more sensitive to the psychomotor and rewarding properties of alcohol, which may depend on neuroplasticity within NAC glutamate transmission. PMID:25916683

  2. Direct inhibition of the longevity promoting factor SKN-1 by Insulin-like signaling in C. elegans

    PubMed Central

    Tullet, Jennifer M. A.; Hertweck, Maren; Hyung An, Jae; Baker, Joseph; Hwang, Ji Yun; Liu, Shu; Oliveira, Riva P.; Baumeister, Ralf; Blackwell, T. Keith

    2008-01-01

    Summary Insulin/IGF-1-like signaling (IIS) is central to growth and metabolism, and has a conserved role in aging. In C. elegans, reductions in IIS increase stress resistance and longevity, effects that require the IIS-inhibited FOXO protein DAF-16. The C. elegans transcription factor SKN-1 also defends against oxidative stress, by mobilizing the conserved Phase 2 detoxification response. Here we show that IIS not only opposes DAF-16, but also directly inhibits SKN-1 in parallel. The IIS kinases AKT-1,-2 and SGK-1 phosphorylate SKN-1, and reduced IIS leads to constitutive SKN-1 nuclear accumulation in the intestine and SKN-1 target gene activation. SKN-1 contributes to the increased stress tolerance and longevity resulting from reduced IIS, and delays aging when expressed transgenically. Furthermore, SKN-1 that is constitutively active increases lifespan independently of DAF-16. Our findings indicate that the transcription network regulated by SKN-1 promotes longevity, and is an important direct target of IIS. PMID:18358814

  3. Chemical genetic screen identifies lithocholic acid as an anti-aging compound that extends yeast chronological life span in a TOR-independent manner, by modulating housekeeping longevity assurance processes

    PubMed Central

    Goldberg, Alexander A.; Richard, Vincent R.; Kyryakov, Pavlo; Bourque, Simon D.; Beach, Adam; Burstein, Michelle T.; Glebov, Anastasia; Koupaki, Olivia; Boukh-Viner, Tatiana; Gregg, Christopher; Juneau, Mylène; English, Ann M.; Thomas, David Y.; Titorenko, Vladimir I.

    2010-01-01

    In chronologically aging yeast, longevity can be extended by administering a caloric restriction (CR) diet or some small molecules. These life-extending interventions target the adaptable target of rapamycin (TOR) and cAMP/protein kinase A (cAMP/PKA) signaling pathways that are under the stringent control of calorie availability. We designed a chemical genetic screen for small molecules that increase the chronological life span of yeast under CR by targeting lipid metabolism and modulating housekeeping longevity pathways that regulate longevity irrespective of the number of available calories. Our screen identifies lithocholic acid (LCA) as one of such molecules. We reveal two mechanisms underlying the life-extending effect of LCA in chronologically aging yeast. One mechanism operates in a calorie availability-independent fashion and involves the LCA-governed modulation of housekeeping longevity assurance pathways that do not overlap with the adaptable TOR and cAMP/PKA pathways. The other mechanism extends yeast longevity under non-CR conditions and consists in LCA-driven unmasking of the previously unknown anti-aging potential of PKA. We provide evidence that LCA modulates housekeeping longevity assurance pathways by suppressing lipid-induced necrosis, attenuating mitochondrial fragmentation, altering oxidation-reduction processes in mitochondria, enhancing resistance to oxidative and thermal stresses, suppressing mitochondria-controlled apoptosis, and enhancing stability of nuclear and mitochondrial DNA. PMID:20622262

  4. Gate control: guard cell regulation by microbial stress.

    PubMed

    McLachlan, Deirdre H; Kopischke, Michaela; Robatzek, Silke

    2014-09-01

    Terrestrial plants rely on stomata, small pores in the leaf surface, for photosynthetic gas exchange and transpiration of water. The stomata, formed by a pair of guard cells, dynamically increase and decrease their volume to control the pore size in response to environmental cues. Stresses can trigger similar or opposing movements: for example, drought induces closure of stomata, whereas many pathogens exploit stomata and cause them to open to facilitate entry into plant tissues. The latter is an active process as stomatal closure is part of the plant's immune response. Stomatal research has contributed much to clarify the signalling pathways of abiotic stress, but guard cell signalling in response to microbes is a relatively new area of research. In this article, we discuss present knowledge of stomatal regulation in response to microbes and highlight common points of convergence, and differences, compared to stomatal regulation by abiotic stresses. We also expand on the mechanisms by which pathogens manipulate these processes to promote disease, for example by delivering effectors to inhibit closure or trigger opening of stomata. The study of pathogen effectors in stomatal manipulation will aid our understanding of guard cell signalling. PMID:25040778

  5. Homocysteine and Familial Longevity: The Leiden Longevity Study

    PubMed Central

    Wijsman, Carolien A.; van Heemst, Diana; Rozing, Maarten P.; Slagboom, P. Eline; Beekman, Marian; de Craen, Anton J. M.; Maier, Andrea B.; Westendorp, Rudi G. J.; Blom, Henk J.; Mooijaart, Simon P.

    2011-01-01

    Homocysteine concentrations are a read-out of methionine metabolism and have been related to changes in lifespan in animal models. In humans, high homocysteine concentrations are an important predictor of age related disease. We aimed to explore the association of homocysteine with familial longevity by testing whether homocysteine is lower in individuals that are genetically enriched for longevity. We measured concentrations of total homocysteine in 1907 subjects from the Leiden Longevity Study consisting of 1309 offspring of nonagenarian siblings, who are enriched with familial factors promoting longevity, and 598 partners thereof as population controls. We found that homocysteine was related to age, creatinine, folate, vitamin B levels and medical history of hypertension and stroke in both groups (all p<0.001). However, levels of homocysteine did not differ between offspring enriched for longevity and their partners, and no differences in the age-related rise in homocysteine levels were found between groups (p for interaction 0.63). The results suggest that homocysteine metabolism is not likely to predict familial longevity. PMID:21408159

  6. Job Stress and Neuropeptide Response Contributing to Food Intake Regulation

    PubMed Central

    Kim, Ki-Woong; Won, Yong Lim; Ko, Kyung Sun

    2015-01-01

    The purpose of the present study is to investigate the correlations between food intake behavior and job stress level and neuropeptide hormone concentrations. Job strain and food intake behavior were first identified using a self-reported questionnaire, concentrations of neuropeptide hormones (adiponectin, brain derived neurotrophic factor [BDNF], leptin, and ghrelin) were determined, and the correlations were analyzed. In the results, job strain showed significant correlations with adiponectin (odds ratio [OR], 1.220; 95% confidence interval [CI], 1.001~1.498; p < 0.05) and BDNF (OR, 0.793; 95% CI, 0.646~0.974; p < 0.05), and ghrelin exhibited a significant correlation with food intake score (OR, 0.911; 95% CI, 0.842~0.985, p < 0.05). These results suggest that job stress affects food intake regulation by altering the physiological concentrations of neuropeptide hormones as well as emotional status. PMID:26877843

  7. Longevity of aeolian megaripples

    NASA Astrophysics Data System (ADS)

    Yizhaq, H.; Katra, I.

    2015-07-01

    Megaripples are distinguished from regular ripples by their larger dimensions and bimodal grain-size distributions. The interplay between wind, grain size and ripple morphology (height and wavelength) controls their development. Two main mechanisms limit megaripple height. The first, megaripple flattening due to winds that are above the fluid threshold of the coarse grains, destroys the armoring layer of the megaripple. The second is megaripple erosion by the impacts of fast-moving, fine saltating grains that propel the coarse grains constituting the armoring layer. For any given wind regime and grain size distribution, the potential megaripple dimensions are limited by these two mechanisms. Here we study the first mechanism and estimate the duration of strong winds (sustained above the fluid threshold) needed to flatten megaripples. Strong gusts of wind, in contrast, cannot destroy the megaripples but can cause ripple migration. Based on data from previous works on megaripples, we find a scaling law between the ripple morphology and the coarse mode of grains at the crest. Using this scaling relation allows us to calculate the wind velocity and duration needed for megaripple flattening. In general, the coarser the particles at the megaripple crest, the stronger the wind needed to flatten the megaripples. Moreover, the greater the strength of the wind required to flatten the megaripples, the lower the recurrence probability. Taken together, these findings increase the longevity of megaripples. We apply the results for a megaripple field in the southern Arava valley (Israel).

  8. The DAF-16 FOXO Transcription Factor Regulates natc-1 to Modulate Stress Resistance in Caenorhabditis elegans, Linking Insulin/IGF-1 Signaling to Protein N-Terminal Acetylation

    PubMed Central

    Warnhoff, Kurt; Murphy, John T.; Kumar, Sandeep; Schneider, Daniel L.; Peterson, Michelle; Hsu, Simon; Guthrie, James; Robertson, J. David; Kornfeld, Kerry

    2014-01-01

    The insulin/IGF-1 signaling pathway plays a critical role in stress resistance and longevity, but the mechanisms are not fully characterized. To identify genes that mediate stress resistance, we screened for C. elegans mutants that can tolerate high levels of dietary zinc. We identified natc-1, which encodes an evolutionarily conserved subunit of the N-terminal acetyltransferase C (NAT) complex. N-terminal acetylation is a widespread modification of eukaryotic proteins; however, relatively little is known about the biological functions of NATs. We demonstrated that loss-of-function mutations in natc-1 cause resistance to a broad-spectrum of physiologic stressors, including multiple metals, heat, and oxidation. The C. elegans FOXO transcription factor DAF-16 is a critical target of the insulin/IGF-1 signaling pathway that mediates stress resistance, and DAF-16 is predicted to directly bind the natc-1 promoter. To characterize the regulation of natc-1 by DAF-16 and the function of natc-1 in insulin/IGF-1 signaling, we analyzed molecular and genetic interactions with key components of the insulin/IGF-1 pathway. natc-1 mRNA levels were repressed by DAF-16 activity, indicating natc-1 is a physiological target of DAF-16. Genetic studies suggested that natc-1 functions downstream of daf-16 to mediate stress resistance and dauer formation. Based on these findings, we hypothesize that natc-1 is directly regulated by the DAF-16 transcription factor, and natc-1 is a physiologically significant effector of the insulin/IGF-1 signaling pathway that mediates stress resistance and dauer formation. These studies identify a novel biological function for natc-1 as a modulator of stress resistance and dauer formation and define a functionally significant downstream effector of the insulin/IGF-1 signaling pathway. Protein N-terminal acetylation mediated by the NatC complex may play an evolutionarily conserved role in regulating stress resistance. PMID:25330323

  9. The role of expectancy and proactive control in stress regulation: A neurocognitive framework for regulation expectation.

    PubMed

    De Raedt, Rudi; Hooley, Jill M

    2016-04-01

    When confronted with stressful or emotionally arousing situations, regulatory abilities should allow us to adaptively cope. However, depressed individuals often have a low sense of perceived control and are characterized by a negative expectation bias regarding their ability to deal with future stressful events. Low expectancy concerning the ability to deal with future stressful events may result in less initiation of proactive control, a crucial mechanism of cognitive control reflecting sustained and anticipatory maintenance of goal-relevant information in the dorsolateral prefrontal cortex to optimize cognitive performance. In this theoretical review we integrate a diverse body of literature. We argue that the expectancy of an individual's regulatory abilities prior to the presentation of an arousing event or stressful task will be related to anticipation and proactive up- or downregulation of specific neurocircuits before the actual encounter with the stressful event occurs, in a manner that can be either adaptive or maladaptive. Moreover, we discuss the important role of self-esteem as well as the ability to accept the situation when coping is not possible. Our approach has implications for a broad range of disorders and conditions in which stress regulation plays a role, and can be used to guide the use of recently developed clinical interventions, as well as to fine-tune interventions to facilitate proactive control. PMID:27064551

  10. RPD3 histone deacetylase and nutrition have distinct but interacting effects on Drosophila longevity.

    PubMed

    Frankel, Stewart; Woods, Jared; Ziafazeli, Tahereh; Rogina, Blanka

    2015-12-01

    Single-gene mutations that extend longevity have revealed regulatory pathways related to aging and longevity. RPD3 is a conserved histone deacetylase (Class I HDAC). Previously we showed that Drosophila rpd3 mutations increase longevity. Here we tested the longevity effects of RPD3 on multiple nutrient levels. Dietary restriction (DR) has additive effects on RPD3-mediated longevity extension, but the effect may be modestly attenuated relative to controls. RPD3 and DR therefore appear to operate by distinct but interacting mechanisms. Since RPD3 regulates transcription, the mRNA levels for two proteins involved in nutrient signaling, 4E-BP and Tor, were examined in rpd3 mutant flies. 4E-BP mRNA was reduced under longevity-increasing conditions. Epistasis between RPD3 and 4E-BP with regard to longevity was then tested. Flies only heterozygous for a mutation in Thor, the 4E-BP gene, have modestly decreased life spans. Flies mutant for both rpd3 and Thor show a superposition of a large RPD3-mediated increase and a small Thor-mediated decrease in longevity at all food levels, consistent with each gene product having distinct effects on life span. However, DR-mediated extension was absent in males carrying both mutations and lessened in females. Our results support the view that multiple discrete but interacting mechanisms regulate longevity. PMID:26647291

  11. RPD3 histone deacetylase and nutrition have distinct but interacting effects on Drosophila longevity

    PubMed Central

    Frankel, Stewart; Woods, Jared; Ziafazeli, Tahereh; Rogina, Blanka

    2015-01-01

    Single-gene mutations that extend longevity have revealed regulatory pathways related to aging and longevity. RPD3 is a conserved histone deacetylase (Class I HDAC). Previously we showed that Drosophila rpd3 mutations increase longevity. Here we tested the longevity effects of RPD3 on multiple nutrient levels. Dietary restriction (DR) has additive effects on RPD3-mediated longevity extension, but the effect may be modestly attenuated relative to controls. RPD3 and DR therefore appear to operate by distinct but interacting mechanisms. Since RPD3 regulates transcription, the mRNA levels for two proteins involved in nutrient signaling, 4E-BP and Tor, were examined in rpd3 mutant flies. 4E-BP mRNA was reduced under longevity-increasing conditions. Epistasis between RPD3 and 4E-BP with regard to longevity was then tested. Flies only heterozygous for a mutation in Thor, the 4E-BP gene, have modestly decreased life spans. Flies mutant for both rpd3 and Thor show a superposition of a large RPD3-mediated increase and a small Thor-mediated decrease in longevity at all food levels, consistent with each gene product having distinct effects on life span. However, DR-mediated extension was absent in males carrying both mutations and lessened in females. Our results support the view that multiple discrete but interacting mechanisms regulate longevity. PMID:26647291

  12. SOD2 functions downstream of Sch9 to extend longevity in yeast.

    PubMed Central

    Fabrizio, Paola; Liou, Lee-Loung; Moy, Vanessa N; Diaspro, Alberto; SelverstoneValentine, Joan; Gralla, Edith Butler; Longo, Valter D

    2003-01-01

    Signal transduction pathways inactivated during periods of starvation are implicated in the regulation of longevity in organisms ranging from yeast to mammals, but the mechanisms responsible for life-span extension are poorly understood. Chronological life-span extension in S. cerevisiae cyr1 and sch9 mutants is mediated by the stress-resistance proteins Msn2/Msn4 and Rim15. Here we show that mitochondrial superoxide dismutase (Sod2) is required for survival extension in yeast. Deletion of SOD2 abolishes life-span extension in sch9Delta mutants and decreases survival in cyr1:mTn mutants. The overexpression of Sods--mitochondrial Sod2 and cytosolic CuZnSod (Sod1)--delays the age-dependent reversible inactivation of mitochondrial aconitase, a superoxide-sensitive enzyme, and extends survival by 30%. Deletion of the RAS2 gene, which functions upstream of CYR1, also doubles the mean life span by a mechanism that requires Msn2/4 and Sod2. These findings link mutations that extend chronological life span in S. cerevisiae to superoxide dismutases and suggest that the induction of other stress-resistance genes regulated by Msn2/4 and Rim15 is required for maximum longevity extension. PMID:12586694

  13. Salmonella Rapidly Regulates Membrane Permeability To Survive Oxidative Stress

    PubMed Central

    van der Heijden, Joris; Reynolds, Lisa A.; Deng, Wanyin; Mills, Allan; Scholz, Roland; Imami, Koshi; Foster, Leonard J.; Duong, Franck

    2016-01-01

    ABSTRACT The outer membrane (OM) of Gram-negative bacteria provides protection against toxic molecules, including reactive oxygen species (ROS). Decreased OM permeability can promote bacterial survival under harsh circumstances and protects against antibiotics. To better understand the regulation of OM permeability, we studied the real-time influx of hydrogen peroxide in Salmonella bacteria and discovered two novel mechanisms by which they rapidly control OM permeability. We found that pores in two major OM proteins, OmpA and OmpC, could be rapidly opened or closed when oxidative stress is encountered and that the underlying mechanisms rely on the formation of disulfide bonds in the periplasmic domain of OmpA and TrxA, respectively. Additionally, we found that a Salmonella mutant showing increased OM permeability was killed more effectively by treatment with antibiotics. Together, these results demonstrate that Gram-negative bacteria regulate the influx of ROS for defense against oxidative stress and reveal novel targets that can be therapeutically targeted to increase bacterial killing by conventional antibiotics. PMID:27507830

  14. Model for how retrograde actin flow regulates adhesion traction stresses.

    PubMed

    Li, Ying; Bhimalapuram, Prabhakar; Dinner, Aaron R

    2010-05-19

    Cells from animals adhere to and exert mechanical forces on their surroundings. Cells must control these forces for many biological processes, and dysfunction can lead to pathologies. How the actions of molecules within a cell are coordinated to regulate the adhesive interaction with the extracellular matrix remains poorly understood. It has been observed that cytoplasmic proteins that link integrin cell-surface receptors with the actin cytoskeleton flow with varying rates from the leading edge toward the center of a cell. Here, we explore theoretically how measurable subcellular traction stresses depend on the local speed of retrograde actin flow. In the model, forces result from the stretching of molecular complexes in response to the drag from the flow; because these complexes break with extension-dependent kinetics, the flow results in a decrease in their number when sufficiently large. Competition between these two effects naturally gives rise to a clutch-like behavior and a nonmonotonic trend in the measured stresses, consistent with recent data for epithelial cells. We use this basic framework to evaluate slip and catch bond mechanisms for integrins; better fits of experimental data are obtained with a catch bond representation. Extension of the model to one comprising multiple molecular interfaces shifts the peak stress to higher speeds. Connections to other models and cell movement are discussed. PMID:21386439

  15. 78 FR 59165 - Orders: Information Reporting With Respect to Stress Testing of Regulated Entities

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-09-26

    ... AGENCY 12 CFR Part 1238 Orders: Information Reporting With Respect to Stress Testing of Regulated... entity) that has total consolidated assets of more than $10 billion to conduct annual stress tests to... advise the regulated entities of the scenarios to be used for the initial stress testing....

  16. p53 regulation upon genotoxic stress: intricacies and complexities

    PubMed Central

    Kumari, Rajni; Kohli, Saishruti; Das, Sanjeev

    2014-01-01

    p53, the revered savior of genomic integrity, receives signals from diverse stress sensors and strategizes to maintain cellular homeostasis. However, the predominance of p53 overshadows the fact that this herculean task is no one-man show; rather, there is a huge army of regulators that reign over p53 at various levels to avoid an unnecessary surge in its levels and sculpt it dynamically to favor one cellular outcome over another. This governance starts right at the time of p53 translation, which is gated by proteins that bind to p53 mRNA and keep a stringent check on p53 protein levels. The same effect is also achieved by ubiquitylases and deubiquitylases that fine-tune p53 turnover and miRNAs that modulate p53 levels, adding precision to this entire scheme. In addition, extensive covalent modifications and differential protein interactions allow p53 to trigger a tailor-made response for a given circumstance. To magnify the marvel, these various tiers of regulation operate simultaneously and in various combinations. In this review, we have tried to provide a glimpse into this bewildering labyrinth. We believe that further studies will result in a better understanding of p53 regulation and that new insights will help unravel many aspects of cancer biology. PMID:27308356

  17. Ca2+-Dependent Endoplasmic Reticulum Stress Regulates Mechanical Stress-Mediated Cartilage Thinning.

    PubMed

    Zhu, M; Zhou, S; Huang, Z; Wen, J; Li, H

    2016-07-01

    Our previous study identified that endoplasmic reticulum stress (ERS) plays a critical role in chondrocyte apoptosis and mandibular cartilage thinning in response to compressive mechanical force, although the underlying mechanisms remain elusive. Because the endoplasmic reticulum (ER) is a primary site of intracellular Ca(2+) storage, we hypothesized that Ca(2+)-dependent ERS might be involved in mechanical stress-mediated mandibular cartilage thinning. In this study, we used in vitro and in vivo models to determine Ca(2+) concentrations, histological changes, subcellular changes, apoptosis, and the expression of ERS markers in mandibular cartilage and chondrocytes. The results showed that in chondrocytes, cytosolic Ca(2+) ([Ca(2+)]i) was dramatically increased by compressive mechanical force. Interestingly, the inhibition of Ca(2+) channels by ryanodine and 2-aminoethoxydiphenyl borate, inhibitors of ryanodine receptors and inositol trisphosphate receptors, respectively, partially rescued mechanical force-mediated mandibular cartilage thinning. Furthermore, chondrocyte apoptosis was also compromised by inhibiting the increase in [Ca(2+)]i that occurred in response to compressive mechanical force. Mechanistically, the ERS induced by compressive mechanical force was also repressed by [Ca(2+)]i inhibition, as demonstrated by a decrease in the expression of the ER stress markers 78 kDa glucose-regulated protein (GRP78) and 94 kDa glucose-regulated protein (GRP94) at both the mRNA and protein levels. Collectively, these data identified [Ca(2+)]i as a critical mediator of the pathological changes that occur in mandibular cartilage under compressive mechanical force and shed light on the treatment of mechanical stress-mediated cartilage degradation. PMID:27053115

  18. The influence of acute stress on the regulation of conditioned fear

    PubMed Central

    Raio, Candace M.; Phelps, Elizabeth A.

    2014-01-01

    Fear learning and regulation is a prominent model for describing the pathogenesis of anxiety disorders and stress-related psychopathology. Fear expression can be modulated using a number of regulatory strategies, including extinction, cognitive emotion regulation, avoidance strategies and reconsolidation. In this review, we examine research investigating the effects of acute stress and stress hormones on these regulatory techniques. We focus on what is known about the impact of stress on the ability to flexibly regulate fear responses that are acquired through Pavlovian fear conditioning. Our primary aim is to explore the impact of stress on fear regulation in humans. Given this, we focus on techniques where stress has been linked to alterations of fear regulation in humans (extinction and emotion regulation), and briefly discuss other techniques (avoidance and reconsolidation) where the impact of stress or stress hormones have been mainly explored in animal models. These investigations reveal that acute stress may impair the persistent inhibition of fear, presumably by altering prefrontal cortex function. Characterizing the effects of stress on fear regulation is critical for understanding the boundaries within which existing regulation strategies are viable in everyday life and can better inform treatment options for those who suffer from anxiety and stress-related psychopathology. PMID:25530986

  19. Lysyl oxidase activity regulates oncogenic stress response and tumorigenesis.

    PubMed

    Wiel, C; Augert, A; Vincent, D F; Gitenay, D; Vindrieux, D; Le Calvé, B; Arfi, V; Lallet-Daher, H; Reynaud, C; Treilleux, I; Bartholin, L; Lelievre, E; Bernard, D

    2013-01-01

    Cellular senescence, a stable proliferation arrest, is induced in response to various stresses. Oncogenic stress-induced senescence (OIS) results in blocked proliferation and constitutes a fail-safe program counteracting tumorigenesis. The events that enable a tumor in a benign senescent state to escape from OIS and become malignant are largely unknown. We show that lysyl oxidase activity contributes to the decision to maintain senescence. Indeed, in human epithelial cell the constitutive expression of the LOX or LOXL2 protein favored OIS escape, whereas inhibition of lysyl oxidase activity was found to stabilize OIS. The relevance of these in vitro observations is supported by in vivo findings: in a transgenic mouse model of aggressive pancreatic ductal adenocarcinoma (PDAC), increasing lysyl oxidase activity accelerates senescence escape, whereas inhibition of lysyl oxidase activity was found to stabilize senescence, delay tumorigenesis, and increase survival. Mechanistically, we show that lysyl oxidase activity favors the escape of senescence by regulating the focal-adhesion kinase. Altogether, our results demonstrate that lysyl oxidase activity participates in primary tumor growth by directly impacting the senescence stability. PMID:24113189

  20. Novel Regulation of Aquaporins during Osmotic Stress1

    PubMed Central

    Vera-Estrella, Rosario; Barkla, Bronwyn J.; Bohnert, Hans J.; Pantoja, Omar

    2004-01-01

    Aquaporin protein regulation and redistribution in response to osmotic stress was investigated. Ice plant (Mesembryanthemum crystallinum) McTIP1;2 (McMIPF) mediated water flux when expressed in Xenopus leavis oocytes. Mannitol-induced water imbalance resulted in increased protein amounts in tonoplast fractions and a shift in protein distribution to other membrane fractions, suggesting aquaporin relocalization. Indirect immunofluorescence labeling also supports a change in membrane distribution for McTIP1;2 and the appearance of a unique compartment where McTIP1;2 is expressed. Mannitol-induced redistribution of McTIP1;2 was arrested by pretreatment with brefeldin A, wortmannin, and cytochalasin D, inhibitors of vesicle trafficking-related processes. Evidence suggests a role for glycosylation and involvement of a cAMP-dependent signaling pathway in McTIP1;2 redistribution. McTIP1;2 redistribution to endosomal compartments may be part of a homeostatic process to restore and maintain cellular osmolarity under osmotic-stress conditions. PMID:15299122

  1. Oxytocin Regulates Stress-Induced Crf Gene Transcription through CREB-Regulated Transcription Coactivator 3

    PubMed Central

    Jurek, Benjamin; Slattery, David A.; Hiraoka, Yuichi; Liu, Ying; Nishimori, Katsuhiko; Aguilera, Greti; van den Burg, Erwin H.

    2015-01-01

    The major regulator of the neuroendocrine stress response in the brain is corticotropin releasing factor (CRF), whose transcription is controlled by CREB and its cofactors CRTC2/3 (TORC2/3). Phosphorylated CRTCs are sequestered in the cytoplasm, but rapidly dephosphorylated and translocated into the nucleus following a stressful stimulus. As the stress response is attenuated by oxytocin (OT), we tested whether OT interferes with CRTC translocation and, thereby, Crf expression. OT (1 nmol, i.c.v.) delayed the stress-induced increase of nuclear CRTC3 and Crf hnRNA levels in the paraventricular nucleus of male rats and mice, but did not affect either parameter in the absence of the stressor. The increase in Crf hnRNA levels at later time points was parallel to elevated nuclear CRTC2/3 levels. A direct effect of Thr4 Gly7-OT (TGOT) on CRTC3 translocation and Crf expression was found in rat primary hypothalamic neurons, amygdaloid (Ar-5), hypothalamic (H32), and human neuroblastoma (Be(2)M17) cell lines. CRTC3, but not CRCT2, knockdown using siRNA in Be(2)M17 cells prevented the effect of TGOT on Crf hnRNA levels. Chromatin-immunoprecipitation demonstrated that TGOT reduced CRTC3, but not CRTC2, binding to the Crf promoter after 10 min of forskolin stimulation. Together, the results indicate that OT modulates CRTC3 translocation, the binding of CRTC3 to the Crf promoter and, ultimately, transcription of the Crf gene. SIGNIFICANCE STATEMENT The neuropeptide oxytocin has been proposed to reduce hypothalamic-pituitary-adrenal (HPA) axis activation during stress. The underlying mechanisms are, however, elusive. In this study we show that activation of the oxytocin receptor in the paraventricular nucleus delays transcription of the gene encoding corticotropin releasing factor (Crf), the main regulator of the stress response. It does so by sequestering the coactivator of the transcription factor CREB, CRTC3, in the cytosol, resulting in reduced binding of CRTC3 to the Crf

  2. Glyphosate resistance does not affect Palmer amaranth seedbank longevity

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A greater understanding of the factors that regulate weed seed return to and persistence in the soil seedbank is needed for the management of difficult to control herbicide resistant weeds. Studies were conducted in Tifton, GA to evaluate the longevity of buried Palmer amaranth seeds and estimate t...

  3. Involvement of Daphnia pulicaria Sir2 in regulating stress response and lifespan

    PubMed Central

    Schumpert, Charles A.; Anderson, Craig; Dudycha, Jeffry L.; Patel, Rekha C.

    2016-01-01

    The ability to appropriately respond to proteotoxic stimuli is a major determinant of longevity and involves induction of various heat shock response (HSR) genes, which are essential to cope with cellular and organismal insults throughout lifespan. The activity of NAD+-dependent deacetylase Sir2, originally discovered in yeast, is known to be essential for effective HSR and longevity. Our previous work on HSR in Daphnia pulicaria indicated a drastic reduction of the HSR in older organisms. In this report we investigate the role of Sir2 in regulating HSR during the lifespan of D. pulicaria. We cloned Daphnia Sir2 open reading frame (ORF) to characterize the enzyme activity and confirmed that the overall function of Sir2 was conserved in Daphnia. The Sir2 mRNA levels increased while the enzyme activity declined with age and considering that Sir2 activity regulates HSR, this explains the previously observed age-dependent decline in HSR. Finally, we tested the effect of Sir2 knockdown throughout adult life by using our new RNA interference (RNAi) method by feeding. Sir2 knockdown severely reduced both the median lifespan as well as significantly increased mortality following heat shock. Our study provides the first characterization and functional study of Daphnia Sir2. PMID:26978617

  4. Involvement of Daphnia pulicaria Sir2 in regulating stress response and lifespan.

    PubMed

    Schumpert, Charles A; Anderson, Craig; Dudycha, Jeffry L; Patel, Rekha C

    2016-02-01

    The ability to appropriately respond to proteotoxic stimuli is a major determinant of longevity and involves induction of various heat shock response (HSR) genes, which are essential to cope with cellular and organismal insults throughout lifespan. The activity of NAD+-dependent deacetylase Sir2, originally discovered in yeast, is known to be essential for effective HSR and longevity. Our previous work on HSR inDaphnia pulicaria indicated a drastic reduction of the HSR in older organisms. In this report we investigate the role of Sir2 in regulating HSR during the lifespan of D. pulicaria. We cloned Daphnia Sir2 open reading frame (ORF) to characterize the enzyme activity and confirmed that the overall function of Sir2 was conserved in Daphnia. The Sir2 mRNA levels increased while the enzyme activity declined with age and considering that Sir2 activity regulates HSR, this explains the previously observed age-dependent decline in HSR. Finally, we tested the effect of Sir2 knockdown throughout adult life by using our new RNA interference (RNAi) method by feeding. Sir2 knockdown severely reduced both the median lifespan as well as significantly increased mortality following heat shock. Our study provides the first characterization and functional study of Daphnia Sir2. PMID:26978617

  5. BAF-1 mobility is regulated by environmental stresses

    PubMed Central

    Bar, Daniel Z.; Davidovich, Maya; Lamm, Ayelet T.; Zer, Hagit; Wilson, Katherine L.; Gruenbaum, Yosef

    2014-01-01

    Barrier to autointegration factor (BAF) is an essential component of the nuclear lamina that binds lamins, LEM-domain proteins, histones, and DNA. Under normal conditions, BAF protein is highly mobile when assayed by fluorescence recovery after photobleaching and fluorescence loss in photobleaching. We report that Caenorhabditis elegans BAF-1 mobility is regulated by caloric restriction, food deprivation, and heat shock. This was not a general response of chromatin-associated proteins, as food deprivation did not affect the mobility of heterochromatin protein HPL-1 or HPL-2. Heat shock also increased the level of BAF-1 Ser-4 phosphorylation. By using missense mutations that affect BAF-1 binding to different partners we find that, overall, the ability of BAF-1 mutants to be immobilized by heat shock in intestinal cells correlated with normal or increased affinity for emerin in vitro. These results show BAF-1 localization and mobility at the nuclear lamina are regulated by stress and unexpectedly reveal BAF-1 immobilization as a specific response to caloric restriction in C. elegans intestinal cells. PMID:24501420

  6. Extended longevity and survivorship during amino-acid starvation in a Drosophila Sir2 mutant heterozygote.

    PubMed

    Slade, Jennifer D; Staveley, Brian E

    2016-05-01

    The regulation of energy homeostasis is pivotal to survive periods of inadequate nutrition. A combination of intricate pathways and proteins are responsible for maximizing longevity during such conditions. The sirtuin deacetylase Sir2 is well conserved from single-celled yeast to mammals, and it controls a number of downstream targets that are active during periods of extreme stress. Overexpression of Sir2 has been established to enhance survival of a number of model organisms undergoing calorie restriction, during which insulin receptor signalling (IRS) is reduced, a condition that itself can enhance survivorship during starvation. Increased Sir2 expression and reduced IRS result in an increase in the activity of the transcription factor foxo, an advantageous activation during stress but lethal when overly active. We have found that a lowered gene dosage of Sir2, in mutant heterozygotes, can extend normal longevity and greatly augment survivorship during amino-acid starvation in Drosophila. Additionally, these mutants, in either heterozygous or homozygous form, do not appear to have any disadvantageous effects upon development or cell growth of the organism unlike IRS mutants. These results may advance the understanding of the biological response to starvation and allow for the development of a model organism to mimic the ability of individuals to tolerate nutrient deprivation. PMID:27074822

  7. Rice OsiSAP7 negatively regulates ABA stress signalling and imparts sensitivity to water-deficit stress in Arabidopsis.

    PubMed

    Sharma, Gunjan; Giri, Jitender; Tyagi, Akhilesh K

    2015-08-01

    Stress associated protein (SAP) genes in plants regulate abiotic stress responses. SAP gene family consists of 18 members in rice. Although their abiotic stress responsiveness is well established, the mechanism of their action is poorly understood. OsiSAP7 was chosen to investigate the mechanism of its action based on the dual nature of its sub-cellular localization preferentially in the nucleus or sub-nuclear speckles upon transient expression in onion epidermal cells. Its expression was down-regulated in rice seedlings under abiotic stresses. OsiSAP7 was localized evenly in the nucleus under unstressed conditions and in sub-nuclear speckles on MG132 treatment. OsiSAP7 exhibits E3 ubiquitin ligase activity in vitro. Abiotic stress responses of OsiSAP7 were assessed by its overexpression in Arabidopsis under the control of a stress inducible promoter rd29A. Stress response assessment was done at seed germination and advanced stages of development. Transgenics were ABA insensitive at seed germination stage and sensitive to water-deficit stress at advanced stage as compared to wild type (WT). They were also impaired in ABA and stress-responsive gene expression. Our study suggests that OsiSAP7 acts as a negative regulator of ABA and water-deficit stress signalling by acting as an E3 ubiquitin ligase. PMID:26089154

  8. Sex differences in cognitive regulation of psychosocial achievement stress: brain and behavior.

    PubMed

    Kogler, Lydia; Gur, Ruben C; Derntl, Birgit

    2015-03-01

    Although cognitive regulation of emotion has been extensively examined, there is a lack of studies assessing cognitive regulation in stressful achievement situations. This study used functional magnetic resonance imaging in 23 females and 20 males to investigate cognitive downregulation of negative, stressful sensations during a frequently used psychosocial stress task. Additionally, subjective responses, cognitive regulation strategies, salivary cortisol, and skin conductance response were assessed. Subjective response supported the experimental manipulation by showing higher anger and negative affect ratings after stress regulation than after the mere exposure to stress. On a neural level, right middle frontal gyrus (MFG) and right superior temporal gyrus (STG) were more strongly activated during regulation than nonregulation, whereas the hippocampus was less activated during regulation. Sex differences were evident: after regulation females expressed higher subjective stress ratings than males, and these ratings were associated with right hippocampal activation. In the nonregulation block, females showed greater activation of the left amygdala and the right STG during stress than males while males recruited the putamen more robustly in this condition. Thus, cognitive regulation of stressful achievement situations seems to induce additional stress, to recruit regions implicated in attention integration and working memory and to deactivate memory retrieval. Stress itself is associated with greater activation of limbic as well as attention areas in females than males. Additionally, activation of the memory system during cognitive regulation of stress is associated with greater perceived stress in females. Sex differences in cognitive regulation strategies merit further investigation that can guide sex sensitive interventions for stress-associated disorders. PMID:25376429

  9. 28 CFR 345.55 - Longevity pay.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 28 Judicial Administration 2 2013-07-01 2013-07-01 false Longevity pay. 345.55 Section 345.55... (FPI) INMATE WORK PROGRAMS Inmate Pay and Benefits § 345.55 Longevity pay. (a) Except as provided in paragraph (b) of this section, an inmate earns longevity pay raises after 18 months spent in FPI work...

  10. 28 CFR 345.55 - Longevity pay.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 28 Judicial Administration 2 2012-07-01 2012-07-01 false Longevity pay. 345.55 Section 345.55... (FPI) INMATE WORK PROGRAMS Inmate Pay and Benefits § 345.55 Longevity pay. (a) Except as provided in paragraph (b) of this section, an inmate earns longevity pay raises after 18 months spent in FPI work...

  11. 28 CFR 345.55 - Longevity pay.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 28 Judicial Administration 2 2010-07-01 2010-07-01 false Longevity pay. 345.55 Section 345.55... (FPI) INMATE WORK PROGRAMS Inmate Pay and Benefits § 345.55 Longevity pay. (a) Except as provided in paragraph (b) of this section, an inmate earns longevity pay raises after 18 months spent in FPI work...

  12. 28 CFR 345.55 - Longevity pay.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 28 Judicial Administration 2 2014-07-01 2014-07-01 false Longevity pay. 345.55 Section 345.55... (FPI) INMATE WORK PROGRAMS Inmate Pay and Benefits § 345.55 Longevity pay. (a) Except as provided in paragraph (b) of this section, an inmate earns longevity pay raises after 18 months spent in FPI work...

  13. 28 CFR 345.55 - Longevity pay.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 28 Judicial Administration 2 2011-07-01 2011-07-01 false Longevity pay. 345.55 Section 345.55... (FPI) INMATE WORK PROGRAMS Inmate Pay and Benefits § 345.55 Longevity pay. (a) Except as provided in paragraph (b) of this section, an inmate earns longevity pay raises after 18 months spent in FPI work...

  14. Longevity of Native Wildflower Seeds

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Wildflowers and forbs used for production, plantings and restoration generally exhibit ‘orthodox’ storage behavior, meaning that longevity can be adjusted by balancing storage relative humidity and temperature. An RH of about 20 to 30% at the storage temperature provides optimum moisture condition...

  15. Longevity Of Dry Film Lubricants

    NASA Technical Reports Server (NTRS)

    Kannel, J. W.; Stockwell, R. D.

    1993-01-01

    Report describes evaluation of dry film lubricants candidate for use in rotary joints of proposed Space Station. Study included experiments and theoretical analyses focused on longevity of sputtered molybdenum disulfide films and ion-plated lead films under conditions partially simulating rolling contact.

  16. Typologies of Extreme Longevity Myths

    PubMed Central

    Young, Robert D.; Desjardins, Bertrand; McLaughlin, Kirsten; Poulain, Michel; Perls, Thomas T.

    2010-01-01

    Purpose. Political, national, religious, and other motivations have led the media and even scientists to errantly accept extreme longevity claims prima facie. We describe various causes of false claims of extraordinary longevity. Design and Methods. American Social Security Death Index files for the period 1980–2009 were queried for individuals with birth and death dates yielding ages 110+ years of age. Frequency was compared to a list of age-validated supercentenarians maintained by the Gerontology Research Group who died during the same time period. Age claims of 110+ years and the age validation experiences of the authors facilitated a list of typologies of false age claims. Results. Invalid age claim rates increase with age from 65% at age 110-111 to 98% by age 115 to 100% for 120+ years. Eleven typologies of false claims were: Religious Authority Myth, Village Elder Myth, Fountain of Youth Myth (substance), Shangri-La Myth (geographic), Nationalist Pride, Spiritual Practice, Familial Longevity, Individual and/or Family Notoriety, Military Service, Administrative Entry Error, and Pension-Social Entitlement Fraud. Conclusions. Understanding various causes of false extreme age claims is important for placing current, past, and future extreme longevity claims in context and for providing a necessary level of skepticism. PMID:21461047

  17. Female Superintendent Longevity in California

    ERIC Educational Resources Information Center

    Rohlfing, Tracy

    2011-01-01

    The purpose of this study was to investigate, through narrative inquiry (Clandinin & Connelly, 2000), the leadership evolution of five female superintendents in California with longevity of 5 or more years in their current school district positions. The research question addressed was, "How do California female superintendents evolve to…

  18. Hypothalamic circuit regulating colonic transit following chronic stress in rats.

    PubMed

    Yoshimoto, Sazu; Cerjak, Diana; Babygirija, Reji; Bulbul, Mehmet; Ludwig, Kirk; Takahashi, Toku

    2012-03-01

    Although acute stress accelerates colonic transit, the effect of chronic stress on colonic transit remains unclear. In this study, rats received repeated restraint stress (chronic homotypic stress) or various types of stress (chronic heterotypic stress) for 5 and 7 days, respectively. Vehicle saline, oxytocin (OXT), OXT receptor antagonist or corticotropin-releasing factor (CRF) receptor antagonists were administered by intracerebroventricular (ICV) injection prior to restraint stress for 90 min. Immediately after the stress exposure, the entire colon was removed and the geometric center (GC) of Na51CrO4 (a nonabsorbable radioactive marker; 0.5 μCi) distribution was calculated to measure the transit. Gene expression of OXT and CRF in the paraventricular nucleus (PVN) was evaluated by in situ hybridization. Accelerated colonic transit with the acute stressor was no longer observed following chronic homotypic stress. This restored colonic transit was reversed by ICV injection of an OXT antagonist. In contrast, chronic heterotypic stress significantly accelerated colonic transit, which was attenuated by ICV injection of OXT and by a CRF receptor 1 antagonist. OXT mRNA expression in the PVN was significantly increased following chronic homotypic stress, but not chronic heterotypic stress. However, CRF mRNA expression in the PVN was significantly increased following acute and chronic heterotypic stress, but not chronic homotypic stress. These results indicate that central OXT and CRF play a pivotal role in mediating the colonic dysmotility following chronic stress in rats. PMID:21936687

  19. Aloin Protects Skin Fibroblasts from Heat Stress-Induced Oxidative Stress Damage by Regulating the Oxidative Defense System.

    PubMed

    Liu, Fu-Wei; Liu, Fu-Chao; Wang, Yu-Ren; Tsai, Hsin-I; Yu, Huang-Ping

    2015-01-01

    Oxidative stress is commonly involved in the pathogenesis of skin damage induced by environmental factors, such as heat stress. Skin fibroblasts are responsible for the connective tissue regeneration and the skin recovery from injury. Aloin, a bioactive compound in Aloe vera, has been reported to have various pharmacological activities, such as anti-inflammatory effects. The aim of this study was to investigate the protective effect of aloin against heat stress-mediated oxidative stress in human skin fibroblast Hs68 cells. Hs68 cells were first incubated at 43°C for 30 min to mimic heat stress. The study was further examined if aloin has any effect on heat stress-induced oxidative stress. We found that aloin protected Hs68 cells against heat stress-induced damage, as assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and lactate dehydrogenase assay. Aloin protected Hs68 cells by regulating reactive oxygen species production and increasing the levels of glutathione, cytosolic and mitochondrial superoxide dismutase. Aloin also prevented the elevation of thiobarbituric acid reactive substances and the reduction of 8-OH-dG induced by heat stress. These results indicated that aloin protected human skin fibroblasts from heat stress-induced oxidative stress damage by regulating the oxidative defense system. PMID:26637174

  20. Aloin Protects Skin Fibroblasts from Heat Stress-Induced Oxidative Stress Damage by Regulating the Oxidative Defense System

    PubMed Central

    Wang, Yu-Ren; Tsai, Hsin-I; Yu, Huang-Ping

    2015-01-01

    Oxidative stress is commonly involved in the pathogenesis of skin damage induced by environmental factors, such as heat stress. Skin fibroblasts are responsible for the connective tissue regeneration and the skin recovery from injury. Aloin, a bioactive compound in Aloe vera, has been reported to have various pharmacological activities, such as anti-inflammatory effects. The aim of this study was to investigate the protective effect of aloin against heat stress-mediated oxidative stress in human skin fibroblast Hs68 cells. Hs68 cells were first incubated at 43°C for 30 min to mimic heat stress. The study was further examined if aloin has any effect on heat stress-induced oxidative stress. We found that aloin protected Hs68 cells against heat stress-induced damage, as assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and lactate dehydrogenase assay. Aloin protected Hs68 cells by regulating reactive oxygen species production and increasing the levels of glutathione, cytosolic and mitochondrial superoxide dismutase. Aloin also prevented the elevation of thiobarbituric acid reactive substances and the reduction of 8-OH-dG induced by heat stress. These results indicated that aloin protected human skin fibroblasts from heat stress-induced oxidative stress damage by regulating the oxidative defense system. PMID:26637174

  1. Genotypically Identifying Wheat Mesophyll Conductance Regulation under Progressive Drought Stress

    PubMed Central

    Olsovska, Katarina; Kovar, Marek; Brestic, Marian; Zivcak, Marek; Slamka, Pavol; Shao, Hong Bo

    2016-01-01

    Photosynthesis limitation by CO2 flow constraints from sub-stomatal cavities to carboxylation sites in chloroplasts under drought stress conditions is, at least in some plant species or crops not fully understood, yet. Leaf mesophyll conductance for CO2 (gm) may considerably affect both photosynthesis and water use efficiency (WUE) in plants under drought conditions. The aim of our study was to detect the responses of gm in leaves of four winter wheat (Triticum aestivum L.) genotypes from different origins under long-term progressive drought. Based on the measurement of gas-exchange parameters the variability of genotypic responses was analyzed at stomatal (stomata closure) and non-stomatal (diffusional and biochemical) limits of net CO2 assimilation rate (AN). In general, progressive drought caused an increasing leaf diffusion resistance against CO2 flow leading to the decrease of AN, gm and stomatal conductance (gs), respectively. Reduction of gm also led to inhibition of carboxylation efficiency (Vcmax). On the basis of achieved results a strong positive relationship between gm and gs was found out indicating a co-regulation and mutual independence of the relationship under the drought conditions. In severely stressed plants, the stomatal limitation of the CO2 assimilation rate was progressively increased, but to a less extent in comparison to gm, while a non-stomatal limitation became more dominant due to the prolonged drought. Mesophyll conductance (gm) seems to be a suitable mechanism and parameter for selection of improved diffusional properties and photosynthetic carbon assimilation in C3 plants, thus explaining their better photosynthetic performance at a whole plant level during periods of drought. PMID:27551283

  2. Genotypically Identifying Wheat Mesophyll Conductance Regulation under Progressive Drought Stress.

    PubMed

    Olsovska, Katarina; Kovar, Marek; Brestic, Marian; Zivcak, Marek; Slamka, Pavol; Shao, Hong Bo

    2016-01-01

    Photosynthesis limitation by CO2 flow constraints from sub-stomatal cavities to carboxylation sites in chloroplasts under drought stress conditions is, at least in some plant species or crops not fully understood, yet. Leaf mesophyll conductance for CO2 (gm) may considerably affect both photosynthesis and water use efficiency (WUE) in plants under drought conditions. The aim of our study was to detect the responses of gm in leaves of four winter wheat (Triticum aestivum L.) genotypes from different origins under long-term progressive drought. Based on the measurement of gas-exchange parameters the variability of genotypic responses was analyzed at stomatal (stomata closure) and non-stomatal (diffusional and biochemical) limits of net CO2 assimilation rate (AN). In general, progressive drought caused an increasing leaf diffusion resistance against CO2 flow leading to the decrease of AN, gm and stomatal conductance (gs), respectively. Reduction of gm also led to inhibition of carboxylation efficiency (Vcmax). On the basis of achieved results a strong positive relationship between gm and gs was found out indicating a co-regulation and mutual independence of the relationship under the drought conditions. In severely stressed plants, the stomatal limitation of the CO2 assimilation rate was progressively increased, but to a less extent in comparison to gm, while a non-stomatal limitation became more dominant due to the prolonged drought. Mesophyll conductance (gm) seems to be a suitable mechanism and parameter for selection of improved diffusional properties and photosynthetic carbon assimilation in C3 plants, thus explaining their better photosynthetic performance at a whole plant level during periods of drought. PMID:27551283

  3. Saccharomyces cerevisiae Tti2 Regulates PIKK Proteins and Stress Response.

    PubMed

    Hoffman, Kyle S; Duennwald, Martin L; Karagiannis, Jim; Genereaux, Julie; McCarton, Alexander S; Brandl, Christopher J

    2016-01-01

    The TTT complex is composed of the three essential proteins Tel2, Tti1, and Tti2 The complex is required to maintain steady state levels of phosphatidylinositol 3-kinase-related kinase (PIKK) proteins, including mTOR, ATM/Tel1, ATR/Mec1, and TRRAP/Tra1, all of which serve as regulators of critical cell signaling pathways. Due to their association with heat shock proteins, and with newly synthesized PIKK peptides, components of the TTT complex may act as cochaperones. Here, we analyze the consequences of depleting the cellular level of Tti2 in Saccharomyces cerevisiae We show that yeast expressing low levels of Tti2 are viable under optimal growth conditions, but the cells are sensitive to a number of stress conditions that involve PIKK pathways. In agreement with this, depleting Tti2 levels decreased expression of Tra1, Mec1, and Tor1, affected their localization and inhibited the stress responses in which these molecules are involved. Tti2 expression was not increased during heat shock, implying that it does not play a general role in the heat shock response. However, steady state levels of Hsp42 increase when Tti2 is depleted, and tti2L187P has a synthetic interaction with exon 1 of the human Huntingtin gene containing a 103 residue polyQ sequence, suggesting a general role in protein quality control. We also find that overexpressing Hsp90 or its cochaperones is synthetic lethal when Tti2 is depleted, an effect possibly due to imbalanced stoichiometry of a complex required for PIKK assembly. These results indicate that Tti2 does not act as a general chaperone, but may have a specialized function in PIKK folding and/or complex assembly. PMID:27172216

  4. Saccharomyces cerevisiae Tti2 Regulates PIKK Proteins and Stress Response

    PubMed Central

    Hoffman, Kyle S.; Duennwald, Martin L.; Karagiannis, Jim; Genereaux, Julie; McCarton, Alexander S.; Brandl, Christopher J.

    2016-01-01

    The TTT complex is composed of the three essential proteins Tel2, Tti1, and Tti2. The complex is required to maintain steady state levels of phosphatidylinositol 3-kinase-related kinase (PIKK) proteins, including mTOR, ATM/Tel1, ATR/Mec1, and TRRAP/Tra1, all of which serve as regulators of critical cell signaling pathways. Due to their association with heat shock proteins, and with newly synthesized PIKK peptides, components of the TTT complex may act as cochaperones. Here, we analyze the consequences of depleting the cellular level of Tti2 in Saccharomyces cerevisiae. We show that yeast expressing low levels of Tti2 are viable under optimal growth conditions, but the cells are sensitive to a number of stress conditions that involve PIKK pathways. In agreement with this, depleting Tti2 levels decreased expression of Tra1, Mec1, and Tor1, affected their localization and inhibited the stress responses in which these molecules are involved. Tti2 expression was not increased during heat shock, implying that it does not play a general role in the heat shock response. However, steady state levels of Hsp42 increase when Tti2 is depleted, and tti2L187P has a synthetic interaction with exon 1 of the human Huntingtin gene containing a 103 residue polyQ sequence, suggesting a general role in protein quality control. We also find that overexpressing Hsp90 or its cochaperones is synthetic lethal when Tti2 is depleted, an effect possibly due to imbalanced stoichiometry of a complex required for PIKK assembly. These results indicate that Tti2 does not act as a general chaperone, but may have a specialized function in PIKK folding and/or complex assembly. PMID:27172216

  5. The Deubiquitylase MATH-33 Controls DAF-16 Stability and Function in Metabolism and Longevity

    PubMed Central

    Heimbucher, Thomas; Liu, Zheng; Bossard, Carine; McCloskey, Richard; Carrano, Andrea C.; Riedel, Christian G.; Tanasa, Bogdan; Klammt, Christian; Fonslow, Bryan R.; Riera, Celine E.; Lillemeier, Bjorn F.; Kemphues, Kenneth; Yates, John R.; O'Shea, Clodagh; Hunter, Tony; Dillin, Andrew

    2015-01-01

    SUMMARY One of the major determinants of aging in organisms ranging from worms to man are FOXO family transcription factors, which are downstream effectors of Insulin/IGF-1 signaling (IIS). The molecular mechanisms that actively promote DAF16/FOXO stability and function are unknown. Here we identify the deubiquitylating enzyme MATH-33 as an essential DAF-16 regulator in IIS, which stabilizes active DAF-16 protein levels and, as a consequence, influences DAF-16 functions, such as metabolism, stress response and longevity in C. elegans. MATH-33 associates with DAF-16 in cellulo and in vitro. MATH-33 functions as a deubiquitylase by actively removing ubiquitin moieties from DAF-16, thus counteracting the action of the RLE-1 E3-ubiquitin ligase. Our findings support a model in which MATH-33 promotes DAF-16 stability in response to decreased IIS by directly modulating its ubiquitylation state, suggesting that regulated oscillations in the stability of DAF-16 protein play an integral role in controlling processes such as metabolism and longevity. PMID:26154057

  6. PCK1 is negatively regulated by bta-miR-26a, and a single-nucleotide polymorphism in the 3' untranslated region is involved in semen quality and longevity of Holstein bulls.

    PubMed

    Huang, Jinming; Guo, Fang; Zhang, Zebin; Zhang, Yuanpei; Wang, Xiuge; Ju, Zhihua; Yang, Chunhong; Wang, Changfa; Hou, Minghai; Zhong, Jifeng

    2016-03-01

    Phosphoenolpyruvate carboxykinase 1 (PCK1) is a multi-functional enzyme that plays important roles in physiological processes, including reproduction. We previously reported that the PCK1 transcript has five splice variants; PCK1-AS4, which lacks exon 5, is enriched in the testis of Holstein bulls. In the present study, we profiled select PCK1 transcript variants in the testis, epididymus, and semen of high- and low-performance bulls, and examined the possibility that microRNAs may be involved in single nucleotide polymorphism (SNP)-mediated modulation of PCK1 expression. PCK1-AS4 abundance is not significantly different between high- and low-performance bulls. Luciferase reporter assays, however, showed that bovine PCK1 expression is repressed by bta-miR-26a in HepG2 hepatocyte cells. One SNP (c. + 2183 G > T) at the miRNA-binding site of PCK1 does not influence PCK1 expression, but is associated with elevated ejaculation volume, fresh sperm motility, and genomic estimated breeding value of longevity, as well as with reduced values of composite index and calving ease. Collectively, the identified 3'-untranslated-region SNP variant highlights the importance of PCK1 in the fecundity of Holstein bulls, and implicates a role for bta-miR-26a in regulating PCK1 abundance. Further study is needed to assess the effects of other genetic variants in 5'-flanking region and exons of PCK1 on enzyme levels in the testis and sperm. Mol. Reprod. Dev. 83: 217-225, 2016. © 2016 Wiley Periodicals, Inc. PMID:26725319

  7. Hypothalamic and dietary control of temperature-mediated longevity

    PubMed Central

    Tabarean, Iustin; Morrison, Brad; Marcondes, Maria Cecilia; Bartfai, Tamas; Conti, Bruno

    2009-01-01

    Temperature is an important modulator of longevity and aging in both poikilotherms and homeotherm animals. In homeotherms, temperature homeostasis is regulated primarily in the preoptic area (POA) of the hypothalamus. This region receives and integrates peripheral, central and environmental signals and maintains a nearly constant core body temperature (Tcore) by regulating the autonomic and hormonal control of heat production and heat dissipation. Temperature sensitive neurons found in the POA are considered key elements of the neuronal circuitry modulating these effects. Nutrient homeostasis is also a hypothalamically regulated modulator of aging as well as one of the signals that can influence Tcore in homeotherms. Investigating the mechanisms of the regulation of nutrient and temperature homeostasis in the hypothalamus is important to understand how these two elements of energy homeostasis influence longevity and aging as well as how aging can affect hypothalamic homeostatic mechanisms. PMID:19631766

  8. Hypothalamic and dietary control of temperature-mediated longevity.

    PubMed

    Tabarean, Iustin; Morrison, Brad; Marcondes, Maria Cecilia; Bartfai, Tamas; Conti, Bruno

    2010-01-01

    Temperature is an important modulator of longevity and aging in both poikilotherms and homeotherm animals. In homeotherms, temperature homeostasis is regulated primarily in the preoptic area (POA) of the hypothalamus. This region receives and integrates peripheral, central and environmental signals and maintains a nearly constant core body temperature (T(core)) by regulating the autonomic and hormonal control of heat production and heat dissipation. Temperature sensitive neurons found in the POA are considered key elements of the neuronal circuitry modulating these effects. Nutrient homeostasis is also a hypothalamically regulated modulator of aging as well as one of the signals that can influence T(core) in homeotherms. Investigating the mechanisms of the regulation of nutrient and temperature homeostasis in the hypothalamus is important to understanding how these two elements of energy homeostasis influence longevity and aging as well as how aging can affect hypothalamic homeostatic mechanisms. PMID:19631766

  9. The Stress Response Regulator AflSkn7 Influences Morphological Development, Stress Response, and Pathogenicity in the Fungus Aspergillus flavus.

    PubMed

    Zhang, Feng; Xu, Gaopo; Geng, Longpo; Lu, Xiaoyan; Yang, Kunlong; Yuan, Jun; Nie, Xinyi; Zhuang, Zhenhong; Wang, Shihua

    2016-01-01

    This study focused on AflSkn7, which is a stress response regulator in the aflatoxin-producing Aspergillus flavus. The ΔAflSkn7 mutants exhibited partially defective conidial formation and a complete inability to generate sclerotia, indicating AflSkn7 affects A. flavus asexual and sexual development. The mutants tolerated osmotic stress but were partially susceptible to the effects of cell wall stress. Additionally, the ΔAflSkn7 mutants were especially sensitive to oxidative stress. These observations confirmed that AflSkn7 influences oxidative stress responses rather than osmotic stress responses. Additionally, AflSkn7 was observed to increase aflatoxin biosynthesis and seed infection rates. These results indicate AflSkn7 affects A. flavus morphological development, stress response, aflatoxin production, and pathogenicity. The results of this study may facilitate the development of new methods to manage A. flavus infections. PMID:27399770

  10. The Stress Response Regulator AflSkn7 Influences Morphological Development, Stress Response, and Pathogenicity in the Fungus Aspergillus flavus

    PubMed Central

    Zhang, Feng; Xu, Gaopo; Geng, Longpo; Lu, Xiaoyan; Yang, Kunlong; Yuan, Jun; Nie, Xinyi; Zhuang, Zhenhong; Wang, Shihua

    2016-01-01

    This study focused on AflSkn7, which is a stress response regulator in the aflatoxin-producing Aspergillus flavus. The ΔAflSkn7 mutants exhibited partially defective conidial formation and a complete inability to generate sclerotia, indicating AflSkn7 affects A. flavus asexual and sexual development. The mutants tolerated osmotic stress but were partially susceptible to the effects of cell wall stress. Additionally, the ΔAflSkn7 mutants were especially sensitive to oxidative stress. These observations confirmed that AflSkn7 influences oxidative stress responses rather than osmotic stress responses. Additionally, AflSkn7 was observed to increase aflatoxin biosynthesis and seed infection rates. These results indicate AflSkn7 affects A. flavus morphological development, stress response, aflatoxin production, and pathogenicity. The results of this study may facilitate the development of new methods to manage A. flavus infections. PMID:27399770

  11. The mysterious relationship between reproduction and longevity

    PubMed Central

    Aguilaniu, Hugo

    2015-01-01

    A negative correlation between fertility and longevity has been documented in many species under a variety of conditions, but the association is not always observed,1 leading to heated discussion about the nature of the reproduction–longevity relationship.2 This debate is further fueled by the fact that no genes or molecules have been clearly shown to link the 2 traits. A recent study by Thondamal et al., in the nematode C. elegans has identified one potential link. The authors showed that the steroid signaling pathway, which regulates reproduction, is activated in response to dietary restriction (DR) and is in fact required for DR-induced lifespan extension.3 Steroid signaling mutants subjected to DR not only failed to undergo lifespan extension but also exhibited altered germline plasticity. Interestingly, the requirement for steroid signaling was bypassed when germline plasticity was restored, suggesting that the DR response is mediated, at least in part, by signals from the germline. In this commentary, I discuss the implications of these findings. Several theories of aging have proposed the existence of an energetic trade-off between reproduction and lifespan,4,5 but mechanistic details are lacking. I propose that revisiting and dissecting at the molecular level the link between reproduction, nutrition, and lifespan, will lead to a better understanding of the aging process and its connection to reproduction. PMID:26430561

  12. Circadian regulation of abiotic stress tolerance in plants

    PubMed Central

    Grundy, Jack; Stoker, Claire; Carré, Isabelle A.

    2015-01-01

    Extremes of temperatures, drought and salinity cause widespread crop losses throughout the world and impose severe limitations on the amount of land that can be used for agricultural purposes. Hence, there is an urgent need to develop crops that perform better under such abiotic stress conditions. Here, we discuss intriguing, recent evidence that circadian clock contributes to plants’ ability to tolerate different types of environmental stress, and to acclimate to them. The clock controls expression of a large fraction of abiotic stress-responsive genes, as well as biosynthesis and signaling downstream of stress response hormones. Conversely, abiotic stress results in altered expression and differential splicing of the clock genes, leading to altered oscillations of downstream stress-response pathways. We propose a range of mechanisms by which this intimate coupling between the circadian clock and environmental stress-response pathways may contribute to plant growth and survival under abiotic stress. PMID:26379680

  13. Genetic variation and human longevity.

    PubMed

    Soerensen, Mette

    2012-05-01

    The overall aim of the PhD project was to elucidate the association of human longevity with genetic variation in major candidate genes and pathways of longevity. Based on a thorough literature and database search we chose to apply a pathway approach; to explore variation in genes composing the DNA damage signaling, DNA repair, GH/IGF-1/insulin signaling and pro-/antioxidant pathways. In addition, 16 genes which did not belong to the core of either pathway, however recurrently regarded as candidate genes of longevity (e.g. APOE), were included. In this way a total of 168 genes were selected for investigation. We decided to explore the genetic variation in the form of single nucleotide polymorphisms (SNPs), a highly investigated type of genetic variation. SNPs having potential functional impact (e.g. affecting binding of transcription factors) were identified, so were specific SNPs in the candidate genes previously published to be associated with human longevity. To cover the majority of the common genetic variation in the 168 gene regions (encoding regions plus 5,000 bp upstream and 1,000 downstream) we applied the tagging SNP approach via the HapMap Consortium. Consequently 1,536 SNPs were selected. The majority of the previous publications on genetic variation and human longevity had employed a case-control study design, e.g. comparing centenarians to middle-aged controls. This type of study design is somehow prone to bias introduced by for instance cohort effects, i.e. differences in characteristics of cases and controls, a kind of bias which is avoided when a prospective cohort is under study. Therefore, we chose to investigate 1,200 individuals of the Danish 1905 birth cohort, which have been followed since 1998 when the members were 92-93 years old. The genetic contribution to human longevity has been estimated to be most profound during the late part of life, thus these oldest-old individuals are excellent for investigating such effect. The follow-up survival

  14. Promoting longevity by maintaining metabolic and proliferative homeostasis.

    PubMed

    Wang, Lifen; Karpac, Jason; Jasper, Heinrich

    2014-01-01

    Aging is characterized by a widespread loss of homeostasis in biological systems. An important part of this decline is caused by age-related deregulation of regulatory processes that coordinate cellular responses to changing environmental conditions, maintaining cell and tissue function. Studies in genetically accessible model organisms have made significant progress in elucidating the function of such regulatory processes and the consequences of their deregulation for tissue function and longevity. Here, we review such studies, focusing on the characterization of processes that maintain metabolic and proliferative homeostasis in the fruitfly Drosophila melanogaster. The primary regulatory axis addressed in these studies is the interaction between signaling pathways that govern the response to oxidative stress, and signaling pathways that regulate cellular metabolism and growth. The interaction between these pathways has important consequences for animal physiology, and its deregulation in the aging organism is a major cause for increased mortality. Importantly, protocols to tune such interactions genetically to improve homeostasis and extend lifespan have been established by work in flies. This includes modulation of signaling pathway activity in specific tissues, including adipose tissue and insulin-producing tissues, as well as in specific cell types, such as stem cells of the fly intestine. PMID:24353210

  15. Promoting longevity by maintaining metabolic and proliferative homeostasis

    PubMed Central

    Wang, Lifen; Karpac, Jason; Jasper, Heinrich

    2014-01-01

    Aging is characterized by a widespread loss of homeostasis in biological systems. An important part of this decline is caused by age-related deregulation of regulatory processes that coordinate cellular responses to changing environmental conditions, maintaining cell and tissue function. Studies in genetically accessible model organisms have made significant progress in elucidating the function of such regulatory processes and the consequences of their deregulation for tissue function and longevity. Here, we review such studies, focusing on the characterization of processes that maintain metabolic and proliferative homeostasis in the fruitfly Drosophila melanogaster. The primary regulatory axis addressed in these studies is the interaction between signaling pathways that govern the response to oxidative stress, and signaling pathways that regulate cellular metabolism and growth. The interaction between these pathways has important consequences for animal physiology, and its deregulation in the aging organism is a major cause for increased mortality. Importantly, protocols to tune such interactions genetically to improve homeostasis and extend lifespan have been established by work in flies. This includes modulation of signaling pathway activity in specific tissues, including adipose tissue and insulin-producing tissues, as well as in specific cell types, such as stem cells of the fly intestine. PMID:24353210

  16. TORC1 Regulates Developmental Responses to Nitrogen Stress via Regulation of the GATA Transcription Factor Gaf1

    PubMed Central

    Laor, Dana; Cohen, Adiel; Kupiec, Martin

    2015-01-01

    ABSTRACT The TOR (target of rapamycin [sirolimus]) is a universally conserved kinase that couples nutrient availability to cell growth. TOR complex 1 (TORC1) in Schizosaccharomyces pombe positively regulates growth in response to nitrogen availability while suppressing cellular responses to nitrogen stress. Here we report the identification of the GATA transcription factor Gaf1 as a positive regulator of the nitrogen stress-induced gene isp7+, via three canonical GATA motifs. We show that under nitrogen-rich conditions, TORC1 positively regulates the phosphorylation and cytoplasmic retention of Gaf1 via the PP2A-like phosphatase Ppe1. Under nitrogen stress conditions when TORC1 is inactivated, Gaf1 becomes dephosphorylated and enters the nucleus. Gaf1 was recently shown to negatively regulate the transcription induction of ste11+, a major regulator of sexual development. Our findings support a model of a two-faceted role of Gaf1 during nitrogen stress. Gaf1 positively regulates genes that are induced early in the response to nitrogen stress, while inhibiting later responses, such as sexual development. Taking these results together, we identify Gaf1 as a novel target for TORC1 signaling and a step-like mechanism to modulate the nitrogen stress response. PMID:26152587

  17. Longevity Genes Revealed by Integrative Analysis of Isoform-Specific daf-16/FoxO Mutants of Caenorhabditis elegans

    PubMed Central

    Chen, Albert Tzong-Yang; Guo, Chunfang; Itani, Omar A.; Budaitis, Breane G.; Williams, Travis W.; Hopkins, Christopher E.; McEachin, Richard C.; Pande, Manjusha; Grant, Ana R.; Yoshina, Sawako; Mitani, Shohei; Hu, Patrick J.

    2015-01-01

    FoxO transcription factors promote longevity across taxa. How they do so is poorly understood. In the nematode Caenorhabditis elegans, the A- and F-isoforms of the FoxO transcription factor DAF-16 extend life span in the context of reduced DAF-2 insulin-like growth factor receptor (IGFR) signaling. To elucidate the mechanistic basis for DAF-16/FoxO-dependent life span extension, we performed an integrative analysis of isoform-specific daf-16/FoxO mutants. In contrast to previous studies suggesting that DAF-16F plays a more prominent role in life span control than DAF-16A, isoform-specific daf-16/FoxO mutant phenotypes and whole transcriptome profiling revealed a predominant role for DAF-16A over DAF-16F in life span control, stress resistance, and target gene regulation. Integration of these datasets enabled the prioritization of a subset of 92 DAF-16/FoxO target genes for functional interrogation. Among 29 genes tested, two DAF-16A-specific target genes significantly influenced longevity. A loss-of-function mutation in the conserved gene gst-20, which is induced by DAF-16A, reduced life span extension in the context of daf-2/IGFR RNAi without influencing longevity in animals subjected to control RNAi. Therefore, gst-20 promotes DAF-16/FoxO-dependent longevity. Conversely, a loss-of-function mutation in srr-4, a gene encoding a seven-transmembrane-domain receptor family member that is repressed by DAF-16A, extended life span in control animals, indicating that DAF-16/FoxO may extend life span at least in part by reducing srr-4 expression. Our discovery of new longevity genes underscores the efficacy of our integrative strategy while providing a general framework for identifying specific downstream gene regulatory events that contribute substantially to transcription factor functions. As FoxO transcription factors have conserved functions in promoting longevity and may be dysregulated in aging-related diseases, these findings promise to illuminate fundamental

  18. Longevity Genes Revealed by Integrative Analysis of Isoform-Specific daf-16/FoxO Mutants of Caenorhabditis elegans.

    PubMed

    Chen, Albert Tzong-Yang; Guo, Chunfang; Itani, Omar A; Budaitis, Breane G; Williams, Travis W; Hopkins, Christopher E; McEachin, Richard C; Pande, Manjusha; Grant, Ana R; Yoshina, Sawako; Mitani, Shohei; Hu, Patrick J

    2015-10-01

    FoxO transcription factors promote longevity across taxa. How they do so is poorly understood. In the nematode Caenorhabditis elegans, the A- and F-isoforms of the FoxO transcription factor DAF-16 extend life span in the context of reduced DAF-2 insulin-like growth factor receptor (IGFR) signaling. To elucidate the mechanistic basis for DAF-16/FoxO-dependent life span extension, we performed an integrative analysis of isoform-specific daf-16/FoxO mutants. In contrast to previous studies suggesting that DAF-16F plays a more prominent role in life span control than DAF-16A, isoform-specific daf-16/FoxO mutant phenotypes and whole transcriptome profiling revealed a predominant role for DAF-16A over DAF-16F in life span control, stress resistance, and target gene regulation. Integration of these datasets enabled the prioritization of a subset of 92 DAF-16/FoxO target genes for functional interrogation. Among 29 genes tested, two DAF-16A-specific target genes significantly influenced longevity. A loss-of-function mutation in the conserved gene gst-20, which is induced by DAF-16A, reduced life span extension in the context of daf-2/IGFR RNAi without influencing longevity in animals subjected to control RNAi. Therefore, gst-20 promotes DAF-16/FoxO-dependent longevity. Conversely, a loss-of-function mutation in srr-4, a gene encoding a seven-transmembrane-domain receptor family member that is repressed by DAF-16A, extended life span in control animals, indicating that DAF-16/FoxO may extend life span at least in part by reducing srr-4 expression. Our discovery of new longevity genes underscores the efficacy of our integrative strategy while providing a general framework for identifying specific downstream gene regulatory events that contribute substantially to transcription factor functions. As FoxO transcription factors have conserved functions in promoting longevity and may be dysregulated in aging-related diseases, these findings promise to illuminate fundamental

  19. A role for seed storage proteins in Arabidopsis seed longevity

    PubMed Central

    Nguyen, Thu-Phuong; Cueff, Gwendal; Hegedus, Dwayne D; Rajjou, Loïc; Bentsink, Leónie

    2015-01-01

    Proteomics approaches have been a useful tool for determining the biological roles and functions of individual proteins and identifying the molecular mechanisms that govern seed germination, vigour and viability in response to ageing. In this work the dry seed proteome of four Arabidopsis thaliana genotypes, that carry introgression fragments at the position of seed longevity quantitative trait loci and as a result display different levels of seed longevity, was investigated. Seeds at two physiological states, after-ripened seeds that had the full germination ability and aged (stored) seeds of which the germination ability was severely reduced, were compared. Aged dry seed proteomes were markedly different from the after-ripened and reflected the seed longevity level of the four genotypes, despite the fact that dry seeds are metabolically quiescent. Results confirmed the role of antioxidant systems, notably vitamin E, and indicated that protection and maintenance of the translation machinery and energy pathways are essential for seed longevity. Moreover, a new role for seed storage proteins (SSPs) was identified in dry seeds during ageing. Cruciferins (CRUs) are the most abundant SSPs in Arabidopsis and seeds of a triple mutant for three CRU isoforms (crua crub cruc) were more sensitive to artificial ageing and their seed proteins were highly oxidized compared with wild-type seeds. These results confirm that oxidation is involved in seed deterioration and that SSPs buffer the seed from oxidative stress, thus protecting important proteins required for seed germination and seedling formation. PMID:26184996

  20. Uncoupling of longevity and paraquat resistance in mutants of the nematode Caenorhabditis elegans.

    PubMed

    Fujii, Michihiko; Tanaka, Nanae; Miki, Kensuke; Hossain, Mohammad Nazir; Endoh, Morio; Ayusawa, Dai

    2005-10-01

    To analyze the relationship between resistance to oxidative stress and longevity, we isolated three novel paraquat-resistant mutants, mev-5, mev-6, and mev-7, from the nematode Caenorhabditis elegans. They all showed the Dyf (defective in dye filling) phenotype, but not always resistance to heat or UV. Life-span extension was observed only in the mev-5 mutant at 26 degrees C. These results indicate that longevity is uncoupled with the phenotype of paraquat resistance. PMID:16244463

  1. Statistical laws for career longevity

    NASA Astrophysics Data System (ADS)

    Petersen, Alexander; Jung, Woo-Sung; Yang, Jae-Suk; Stanley, H. Eugene

    2009-03-01

    Career length distinguishes successful long tenures from unsuccessful short stints, and partially reflects the contributions of an employee to the goals of the employer. In some professions, there are well-defined metrics that quantify career longevity, prowess, and productivity, which together contribute to the overall success rating for an individual employee. In this talk, I motivate a stochastic model for career development that relies on two key ingredients, random progress within the career and random stopping times terminating the career. This model is exactly solvable, predicting the probability density function (pdf) of career longevity, characterized by two parameters, α and xc. The parameter α quantifies the power-law scaling of the pdf, which is terminated by an exponential cutoff after a crossover value xc, representing the mean career lifetime. We test the model with the large quantity of empirical data available for several professional sports leagues, American baseball, Korean baseball, American basketball, and English soccer, finding excellent agreement with the model's predictions. In all, the generality of the model suggests that there may be common stochastic forces that underly progress, success, and longevity in various professions.

  2. Neuroendocrine circuits governing energy balance and stress regulation: functional overlap and therapeutic implications

    PubMed Central

    Ulrich-Lai, Yvonne M.; Ryan, Karen K.

    2014-01-01

    Significant co-morbidities between obesity-related metabolic disease and stress-related psychological disorders suggest important functional interactions between energy balance and brain stress integration. Largely overlapping neural circuits control these systems, and this anatomical arrangement optimizes opportunities for mutual influence. Here we first review the current literature identifying effects of metabolic neuroendocrine signals on stress regulation, and vice versa. Next, the contributions of reward driven food intake to these metabolic and stress interactions are discussed. Lastly, we consider the inter-relationships among metabolism, stress and reward in light of their important implications in the development of therapies for metabolism- or stress-related disease. PMID:24630812

  3. Longevity and skeletal muscle mass: the role of IGF signalling, the sirtuins, dietary restriction and protein intake.

    PubMed

    Sharples, Adam P; Hughes, David C; Deane, Colleen S; Saini, Amarjit; Selman, Colin; Stewart, Claire E

    2015-08-01

    Advancing age is associated with a progressive loss of skeletal muscle (SkM) mass and function. Given the worldwide aging demographics, this is a major contributor to morbidity, escalating socio-economic costs and ultimately mortality. Previously, it has been established that a decrease in regenerative capacity in addition to SkM loss with age coincides with suppression of insulin/insulin-like growth factor signalling pathways. However, genetic or pharmacological modulations of these highly conserved pathways have been observed to significantly enhance life and healthspan in various species, including mammals. This therefore provides a controversial paradigm in which reduced regenerative capacity of skeletal muscle tissue with age potentially promotes longevity of the organism. This paradox will be assessed and considered in the light of the following: (i) the genetic knockout, overexpression and pharmacological models that induce lifespan extension (e.g. IRS-1/s6K KO, mTOR inhibition) versus the important role of these signalling pathways in SkM growth and adaptation; (ii) the role of the sirtuins (SIRTs) in longevity versus their emerging role in SkM regeneration and survival under catabolic stress; (iii) the role of dietary restriction and its impact on longevity versus skeletal muscle mass regulation; (iv) the crosstalk between cellular energy metabolism (AMPK/TSC2/SIRT1) and survival (FOXO) versus growth and repair of SkM (e.g. AMPK vs. mTOR); and (v) the impact of protein feeding in combination with dietary restriction will be discussed as a potential intervention to maintain SkM mass while increasing longevity and enabling healthy aging. PMID:25866088

  4. Drosophila Longevity Assurance Conferred by Reduced Insulin Receptor Substrate Chico Partially Requires d4eBP

    PubMed Central

    Bai, Hua; Post, Stephanie; Kang, Ping; Tatar, Marc

    2015-01-01

    Mutations of the insulin/IGF signaling (IIS) pathway extend Drosophila lifespan. Based on genetic epistasis analyses, this longevity assurance is attributed to downstream effects of the FOXO transcription factor. However, as reported FOXO accounts for only a portion of the observed longevity benefit, suggesting there are additional outputs of IIS to mediate aging. One candidate is target of rapamycin complex 1 (TORC1). Reduced TORC1 activity is reported to slow aging, whereas reduced IIS is reported to repress TORC1 activity. The eukaryotic translation initiation factor 4E binding protein (4E-BP) is repressed by TORC1, and activated 4E-BP is reported to increase Drosophila lifespan. Here we use genetic epistasis analyses to test whether longevity assurance mutants of chico, the Drosophila insulin receptor substrate homolog, require Drosophila d4eBP to slow aging. In chico heterozygotes, which are robustly long-lived, d4eBP is required but not sufficient to slow aging. Remarkably, d4eBP is not required or sufficient for chico homozygotes to extend longevity. Likewise, chico heterozygote females partially require d4eBP to preserve age-dependent locomotion, and both chico genotypes require d4eBP to improve stress-resistance. Reproduction and most measures of growth affected by either chico genotype are always independent of d4eBP. In females, chico heterozygotes paradoxically produce more rather than less phosphorylated 4E-BP (p4E-BP). Altered IRS function within the IIS pathway of Drosophila appears to have partial, conditional capacity to regulate aging through an unconventional interaction with 4E-BP. PMID:26252766

  5. Longevity and skeletal muscle mass: the role of IGF signalling, the sirtuins, dietary restriction and protein intake

    PubMed Central

    Sharples, Adam P; Hughes, David C; Deane, Colleen S; Saini, Amarjit; Selman, Colin; Stewart, Claire E

    2015-01-01

    Advancing age is associated with a progressive loss of skeletal muscle (SkM) mass and function. Given the worldwide aging demographics, this is a major contributor to morbidity, escalating socio-economic costs and ultimately mortality. Previously, it has been established that a decrease in regenerative capacity in addition to SkM loss with age coincides with suppression of insulin/insulin-like growth factor signalling pathways. However, genetic or pharmacological modulations of these highly conserved pathways have been observed to significantly enhance life and healthspan in various species, including mammals. This therefore provides a controversial paradigm in which reduced regenerative capacity of skeletal muscle tissue with age potentially promotes longevity of the organism. This paradox will be assessed and considered in the light of the following: (i) the genetic knockout, overexpression and pharmacological models that induce lifespan extension (e.g. IRS-1/s6K KO, mTOR inhibition) versus the important role of these signalling pathways in SkM growth and adaptation; (ii) the role of the sirtuins (SIRTs) in longevity versus their emerging role in SkM regeneration and survival under catabolic stress; (iii) the role of dietary restriction and its impact on longevity versus skeletal muscle mass regulation; (iv) the crosstalk between cellular energy metabolism (AMPK/TSC2/SIRT1) and survival (FOXO) versus growth and repair of SkM (e.g. AMPK vs. mTOR); and (v) the impact of protein feeding in combination with dietary restriction will be discussed as a potential intervention to maintain SkM mass while increasing longevity and enabling healthy aging. PMID:25866088

  6. Regulation of the aging process by autophagy.

    PubMed

    Salminen, Antero; Kaarniranta, Kai

    2009-05-01

    Autophagy is involved in cellular protein and organelle degradation, which is mediated by the lysosomal pathway. Autophagocytosis has a key role in cellular housekeeping by removing damaged organelles. During aging, the efficiency of autophagic degradation declines and intracellular waste products accumulate. In Caenorhabditis elegans, there is clear evidence that lifespan is linked to the capacity to regulate autophagy. Recent studies have revealed that the same signaling factors regulate both aging and autophagocytosis, thus highlighting the role of autophagy in the regulation of aging and age-related degenerative diseases. Here, we examine in detail the interactions of the signaling network involving longevity factors SIRT1, mTOR, FoxO3, NF-kappaB and p53 in the regulation of autophagy. We discuss the possibility that these well-known stress resistance and longevity factors regulate the aging process via autophagy. PMID:19380253

  7. Regulation of OSU-03012 toxicity by ER stress proteins and ER stress inducing drugs

    PubMed Central

    Booth, Laurence; Roberts, Jane L.; Cruickshanks, Nichola; Grant, Steven; Poklepovic, Andrew; Dent, Paul

    2014-01-01

    The present studies examined the toxic interaction between the non-coxib celecoxib derivative OSU-03012 and phosphodiesterase 5 (PDE5) inhibitors, and to determine the roles of endoplasmic reticulum stress response regulators in cell survival. PDE5 inhibitors interacted in a greater than additive fashion with OSU-03012 to kill parental glioma and stem-like glioma cells. Knock down of the endoplasmic reticulum stress response proteins IRE1 or XBP1 enhanced the lethality of OSU-03012, and of [OSU-03012 + PDE5 inhibitor] treatment. Pan-caspase and caspase 9 inhibition did not alter OSU-03012 lethality but did abolish enhanced killing in the absence of IRE1 or XBP1. Expression of the mitochondrial protective protein BCL-XL or the caspase 8 inhibitor c-FLIP-s, or knock down of death receptor CD95 or the death receptor – caspase 8 linker protein FADD, suppressed killing by [OSU-03012 + PDE5 inhibitor] treatment. CD95 activation was blocked by the nitric oxide synthase inhibitor L-NAME. Knock down of the autophagy regulatory proteins Beclin1 or ATG5 protected cells from OSU-03012 and of [OSU-03012 + PDE5 inhibitor] toxicity. Knock down of IRE1 enhanced OSU-03012/[OSU-03012 + PDE5 inhibitor] –induced JNK activation and inhibition of JNK suppressed the elevated killing caused by IRE1 knock down. Knock down of CD95 blunted JNK activation. Collectively our data demonstrates that PDE5 inhibitors recruit death receptor signaling to enhance OSU-03012 toxicity in GBM cells. PMID:25103559

  8. Pleiotropic Cellular Functions of PARP1 in Longevity and Aging: Genome Maintenance Meets Inflammation

    PubMed Central

    Mangerich, Aswin; Bürkle, Alexander

    2012-01-01

    Aging is a multifactorial process that depends on diverse molecular and cellular mechanisms, such as genome maintenance and inflammation. The nuclear enzyme poly(ADP-ribose) polymerase 1 (PARP1), which catalyzes the synthesis of the biopolymer poly(ADP-ribose), exhibits an essential role in both processes. On the one hand, PARP1 serves as a genomic caretaker as it participates in chromatin remodelling, DNA repair, telomere maintenance, resolution of replicative stress, and cell cycle control. On the other hand, PARP1 acts as a mediator of inflammation due to its function as a regulator of NF-κB and other transcription factors and its potential to induce cell death. Consequently, PARP1 represents an interesting player in several aging mechanisms and is discussed as a longevity assurance factor on the one hand and an aging-promoting factor on the other hand. Here, we review the molecular mechanisms underlying the various roles of PARP1 in longevity and aging with special emphasis on cellular studies and we briefly discuss the results in the context of in vivo studies in mice and humans. PMID:23050038

  9. 77 FR 60948 - Stress Testing of Regulated Entities

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-10-05

    ... Insurance Office while drafting this proposed rule. \\3\\ See 77 FR 594, 625-633, ``Enhanced Prudential Standards and Early Remediation Requirements for Covered Companies.'' \\4\\ 77 FR 3166, ``Annual Stress Test.'' \\5\\ 77 FR 3408, ``Annual Stress Test.'' V. Differences Between Banks and Enterprises Section 1313...

  10. Regulation Systems of Bacteria such as Escherichia coli in Response to Nutrient Limitation and Environmental Stresses

    PubMed Central

    Shimizu, Kazuyuki

    2013-01-01

    An overview was made to understand the regulation system of a bacterial cell such as Escherichia coli in response to nutrient limitation such as carbon, nitrogen, phosphate, sulfur, ion sources, and environmental stresses such as oxidative stress, acid shock, heat shock, and solvent stresses. It is quite important to understand how the cell detects environmental signals, integrate such information, and how the cell system is regulated. As for catabolite regulation, F1,6B P (FDP), PEP, and PYR play important roles in enzyme level regulation together with transcriptional regulation by such transcription factors as Cra, Fis, CsrA, and cAMP-Crp. αKG plays an important role in the coordinated control between carbon (C)- and nitrogen (N)-limitations, where αKG inhibits enzyme I (EI) of phosphotransferase system (PTS), thus regulating the glucose uptake rate in accordance with N level. As such, multiple regulation systems are co-ordinated for the cell synthesis and energy generation against nutrient limitations and environmental stresses. As for oxidative stress, the TCA cycle both generates and scavenges the reactive oxygen species (ROSs), where NADPH produced at ICDH and the oxidative pentose phosphate pathways play an important role in coping with oxidative stress. Solvent resistant mechanism was also considered for the stresses caused by biofuels and biochemicals production in the cell. PMID:24958385

  11. Physiological Regulation of Stress in Referred Adolescents: The Role of the Parent-Adolescent Relationship

    ERIC Educational Resources Information Center

    Willemen, Agnes M.; Schuengel, Carlo; Koot, Hans M.

    2009-01-01

    Background: Psychopathology in youth appears to be linked to deficits in regulating affective responses to stressful situations. In children, high-quality parental support facilitates affect regulation. However, in adolescence, the role of parent-child interaction in the regulation of affect is unclear. This study examined physiological reactivity…

  12. Regulation of Stress Responses and Translational Control by Coronavirus

    PubMed Central

    Fung, To Sing; Liao, Ying; Liu, Ding Xiang

    2016-01-01

    Similar to other viruses, coronavirus infection triggers cellular stress responses in infected host cells. The close association of coronavirus replication with the endoplasmic reticulum (ER) results in the ER stress responses, which impose a challenge to the viruses. Viruses, in turn, have come up with various mechanisms to block or subvert these responses. One of the ER stress responses is inhibition of the global protein synthesis to reduce the amount of unfolded proteins inside the ER lumen. Viruses have evolved the capacity to overcome the protein translation shutoff to ensure viral protein production. Here, we review the strategies exploited by coronavirus to modulate cellular stress response pathways. The involvement of coronavirus-induced stress responses and translational control in viral pathogenesis will also be briefly discussed. PMID:27384577

  13. Regulation of Stress Responses and Translational Control by Coronavirus.

    PubMed

    Fung, To Sing; Liao, Ying; Liu, Ding Xiang

    2016-01-01

    Similar to other viruses, coronavirus infection triggers cellular stress responses in infected host cells. The close association of coronavirus replication with the endoplasmic reticulum (ER) results in the ER stress responses, which impose a challenge to the viruses. Viruses, in turn, have come up with various mechanisms to block or subvert these responses. One of the ER stress responses is inhibition of the global protein synthesis to reduce the amount of unfolded proteins inside the ER lumen. Viruses have evolved the capacity to overcome the protein translation shutoff to ensure viral protein production. Here, we review the strategies exploited by coronavirus to modulate cellular stress response pathways. The involvement of coronavirus-induced stress responses and translational control in viral pathogenesis will also be briefly discussed. PMID:27384577

  14. Longevity of Mass-Produced Bactrocera tryoni (Diptera: Tephritidae) Held Without Food or Water.

    PubMed

    Dominiak, Bernard C; Sundaralingam, Selliah; Jiang, Laura; Nicol, Helen I

    2014-12-01

    The sterile insect technique is used to manage or control fruit flies throughout the world. The technique relies on large scale production before delivery to release managers. As part of the mass production phase, there are many quality control tests to demonstrate and maintain high quality pupae and flies. One highly desirable characteristic is adults with a long life so that these adults can reach sexual maturity and sterile males mate with wild fertile flies in the field and thus produce no viable offspring. Originally longevity was assessed allowing adults to have unlimited access to food and water. As quality and longevity increased, this methodology added significantly to workload and space demands and many facilities moved to testing longevity under stress where no food or water was provided. Here we examined >27,000 Queensland fruit fly Bactrocera tryoni (Froggatt) from 160 weekly production batches from July 2004 to October 2009 where flies were not provided food or water. The mean longevity was 54.4 ± SE hours. Longevity was significantly shorter from August to March, and the longevity was significantly longer in June. Longevity was not related to pupal weight, contrary to expectations. Weights were significantly lower in June and highest in summer. PMID:26470075

  15. The role of emotion regulation and cognitive control in the association between mindfulness disposition and stress.

    PubMed

    Prakash, Ruchika Shaurya; Hussain, Mariam A; Schirda, Brittney

    2015-03-01

    Dispositional mindfulness is associated with lower levels of perceived stress, with increased emotional regulation and cognitive control proposed as mechanisms underlying these stress-buffering effects of mindfulness. Within aging, these controlled processes represent paradoxically divergent trajectories such that older adults exhibit reduced cognitive control capacities, while emotional regulation abilities are well maintained, and at times enhanced. Our study seeks to examine the role of emotional regulation and cognitive control as possible mediators of the association between mindfulness and perceived stress. In addition, we examined age-related differences in the observed associations among mindfulness, stress, and controlled regulatory behavior. Fifty older adults and fifty young adults were recruited for the study and completed self-report measures assessing mindfulness disposition, perceived stress, and emotional regulation. In addition, computerized measures of cognitive control assessing working memory, inhibitory control, and set-shifting were also administered. We hypothesized a negative correlation between mindfulness disposition and perceived stress such that participants reporting higher levels of dispositional mindfulness would report lower stress. In addition, we hypothesized increased difficulties in emotion regulation and lower cognitive control to mediate this relationship. Corroborating previous literature, results revealed that mindfulness disposition and perceived stress were negatively correlated in both groups. However, emotion regulation, but not cognitive control, was found to mediate the relationship between mindfulness and perceived stress in both groups. Age group was not found to moderate the observed effects. Our findings reveal the role of enhanced emotional regulation abilities as a potential factor associated with the stress-reducing capacity of dispositional mindfulness. PMID:25545683

  16. Molecular aspects of stress-gene regulation during spaceflight

    NASA Technical Reports Server (NTRS)

    Paul, Anna-Lisa; Ferl, Robert J.

    2002-01-01

    Spaceflight-associated stress has been the topic of investigation since the first terrestrial organisms were exposed to this unique environment. Organisms that evolved under the selection pressures of earth-normal environments can perceive spaceflight as a stress, either directly because gravity influences an intrinsic biological process, or indirectly because of secondary effects imparted by spaceflight upon environmental conditions. Different organisms and even different organs within an organism adapt to a spaceflight environment with a diversity of tactics. Plants are keenly sensitive to gravity for directed development, and are also sensitive to other stresses associated with closed-system spaceflight environments. Within the past decade, the tools of molecular biology have begun to provide a sophisticated evaluation of spaceflight-associated stress and the genetic responses that accompany metabolic adaptation to spaceflight.

  17. Regulation of the Adrenal Cortex Function During Stress

    NASA Technical Reports Server (NTRS)

    Soliman, K. F. A.

    1978-01-01

    A proposal to study the function of the adrenal gland in the rat during stress is presented. In the proposed project, three different phases of experimentation will be undertaken. The first phase includes establishment of the circadian rhythm of both brain amines and glucocoticoids, under normal conditions and under chronic and acute stressful conditions. The second phase includes the study of the pharmacokinetics of glucocorticoid binding under normal and stress conditions. The third phase includes brain uptake and binding under different experimental conditions. In the outlined experiments brain biogenic amines will be evaluated, adrenal functions will be measured and stress effect on those parameters will be studied. It is hoped that this investigation can explain some of the complex relationships between the brain neurotransmitter and adrenal function.

  18. Regulation of the hypothalamic-pituitary-adrenocortical stress response

    PubMed Central

    Herman, James P.; McKlveen, Jessica M.; Ghosal, Sriparna; Kopp, Brittany; Wulsin, Aynara; Makinson, Ryan; Scheimann, Jessie; Myers, Brent

    2016-01-01

    The hypothalamo-pituitary-adrenocortical (HPA axis) is required for stress adaptation. Activation of the HPA axis causes secretion of glucocorticoids, which act on multiple organ systems to redirect energy resources to meet real or anticipated demand. The HPA stress response is driven primarily by neural mechanisms, invoking corticotrophin releasing hormone (CRH) release from hypothalamic paraventricular nucleus (PVN) neurons. Pathways activating CRH release are stressor dependent: reactive responses to homeostatic disruption frequently involve direct noradrenergic or peptidergic drive of PVN neurons by sensory relays, whereas anticipatory responses use oligosynaptic pathways originating in upstream limbic structures. Anticipatory responses are driven largely by disinhibition, mediated by trans-synaptic silencing of tonic PVN inhibition via GABAergic neurons in the amygdala. Stress responses are inhibited by negative feedback mechanisms, whereby glucocorticoids act to diminish drive (brainstem), promote trans-synaptic inhibition by limbic structures (e.g, hippocampus). Glucocorticoids also act at the PVN to rapidly inhibit CRH neuronal activity via membrane glucocorticoid receptors. Chronic stress-induced activation of the HPA axis takes many forms (chronic basal hypersecretion, sensitized stress responses, even adrenal exhaustion), with manifestation dependent upon factors such as stressor chronicity, intensity, frequency and modality. Neural mechanisms driving chronic stress responses can be distinct from those controlling acute reactions, including recruitment of novel limbic, hypothalamic and brainstem circuits. Importantly, an individual’s response to acute or chronic stress is determined by numerous factors, including genetics, early life experience, environmental conditions, sex and age. The context in which stressors occur will determine whether an individual’s acute or chronic stress responses are adaptive or maladaptive (pathological). PMID:27065163

  19. Gut Microbiota and Extreme Longevity.

    PubMed

    Biagi, Elena; Franceschi, Claudio; Rampelli, Simone; Severgnini, Marco; Ostan, Rita; Turroni, Silvia; Consolandi, Clarissa; Quercia, Sara; Scurti, Maria; Monti, Daniela; Capri, Miriam; Brigidi, Patrizia; Candela, Marco

    2016-06-01

    The study of the extreme limits of human lifespan may allow a better understanding of how human beings can escape, delay, or survive the most frequent age-related causes of morbidity, a peculiarity shown by long-living individuals. Longevity is a complex trait in which genetics, environment, and stochasticity concur to determine the chance to reach 100 or more years of age [1]. Because of its impact on human metabolism and immunology, the gut microbiome has been proposed as a possible determinant of healthy aging [2, 3]. Indeed, the preservation of host-microbes homeostasis can counteract inflammaging [4], intestinal permeability [5], and decline in bone and cognitive health [6, 7]. Aiming at deepening our knowledge on the relationship between the gut microbiota and a long-living host, we provide for the first time the phylogenetic microbiota analysis of semi-supercentenarians, i.e., 105-109 years old, in comparison to adults, elderly, and centenarians, thus reconstructing the longest available human microbiota trajectory along aging. We highlighted the presence of a core microbiota of highly occurring, symbiotic bacterial taxa (mostly belonging to the dominant Ruminococcaceae, Lachnospiraceae, and Bacteroidaceae families), with a cumulative abundance decreasing along with age. Aging is characterized by an increasing abundance of subdominant species, as well as a rearrangement in their co-occurrence network. These features are maintained in longevity and extreme longevity, but peculiarities emerged, especially in semi-supercentenarians, describing changes that, even accommodating opportunistic and allochthonous bacteria, might possibly support health maintenance during aging, such as an enrichment and/or higher prevalence of health-associated groups (e.g., Akkermansia, Bifidobacterium, and Christensenellaceae). PMID:27185560

  20. Caveolin-1 regulates shear stress-dependent activation of extracellular signal-regulated kinase

    NASA Technical Reports Server (NTRS)

    Park, H.; Go, Y. M.; Darji, R.; Choi, J. W.; Lisanti, M. P.; Maland, M. C.; Jo, H.

    2000-01-01

    Fluid shear stress activates a member of the mitogen-activated protein (MAP) kinase family, extracellular signal-regulated kinase (ERK), by mechanisms dependent on cholesterol in the plasma membrane in bovine aortic endothelial cells (BAEC). Caveolae are microdomains of the plasma membrane that are enriched with cholesterol, caveolin, and signaling molecules. We hypothesized that caveolin-1 regulates shear activation of ERK. Because caveolin-1 is not exposed to the outside, cells were minimally permeabilized by Triton X-100 (0.01%) to deliver a neutralizing, polyclonal caveolin-1 antibody (pCav-1) inside the cells. pCav-1 then bound to caveolin-1 and inhibited shear activation of ERK but not c-Jun NH(2)-terminal kinase. Epitope mapping studies showed that pCav-1 binds to caveolin-1 at two regions (residues 1-21 and 61-101). When the recombinant proteins containing the epitopes fused to glutathione-S-transferase (GST-Cav(1-21) or GST-Cav(61-101)) were preincubated with pCav-1, only GST-Cav(61-101) reversed the inhibitory effect of the antibody on shear activation of ERK. Other antibodies, including m2234, which binds to caveolin-1 residues 1-21, had no effect on shear activation of ERK. Caveolin-1 residues 61-101 contain the scaffolding and oligomerization domains, suggesting that binding of pCav-1 to these regions likely disrupts the clustering of caveolin-1 or its interaction with signaling molecules involved in the shear-sensitive ERK pathway. We suggest that caveolae-like domains play a critical role in the mechanosensing and/or mechanosignal transduction of the ERK pathway.

  1. MicroRNA Predictors of Longevity in Caenorhabditis elegans

    PubMed Central

    Pincus, Zachary; Smith-Vikos, Thalyana; Slack, Frank J.

    2011-01-01

    Neither genetic nor environmental factors fully account for variability in individual longevity: genetically identical invertebrates in homogenous environments often experience no less variability in lifespan than outbred human populations. Such variability is often assumed to result from stochasticity in damage accumulation over time; however, the identification of early-life gene expression states that predict future longevity would suggest that lifespan is least in part epigenetically determined. Such “biomarkers of aging,” genetic or otherwise, nevertheless remain rare. In this work, we sought early-life differences in organismal robustness in unperturbed individuals and examined the utility of microRNAs, known regulators of lifespan, development, and robustness, as aging biomarkers. We quantitatively examined Caenorhabditis elegans reared individually in a novel apparatus and observed throughout their lives. Early-to-mid–adulthood measures of homeostatic ability jointly predict 62% of longevity variability. Though correlated, markers of growth/muscle maintenance and of metabolic by-products (“age pigments”) report independently on lifespan, suggesting that graceful aging is not a single process. We further identified three microRNAs in which early-adulthood expression patterns individually predict up to 47% of lifespan differences. Though expression of each increases throughout this time, mir-71 and mir-246 correlate with lifespan, while mir-239 anti-correlates. Two of these three microRNA “biomarkers of aging” act upstream in insulin/IGF-1–like signaling (IIS) and other known longevity pathways, thus we infer that these microRNAs not only report on but also likely determine longevity. Thus, fluctuations in early-life IIS, due to variation in these microRNAs and from other causes, may determine individual lifespan. PMID:21980307

  2. Lithium Promotes Longevity through GSK3/NRF2-Dependent Hormesis

    PubMed Central

    Castillo-Quan, Jorge Iván; Li, Li; Kinghorn, Kerri J.; Ivanov, Dobril K.; Tain, Luke S.; Slack, Cathy; Kerr, Fiona; Nespital, Tobias; Thornton, Janet; Hardy, John; Bjedov, Ivana; Partridge, Linda

    2016-01-01

    Summary The quest to extend healthspan via pharmacological means is becoming increasingly urgent, both from a health and economic perspective. Here we show that lithium, a drug approved for human use, promotes longevity and healthspan. We demonstrate that lithium extends lifespan in female and male Drosophila, when administered throughout adulthood or only later in life. The life-extending mechanism involves the inhibition of glycogen synthase kinase-3 (GSK-3) and activation of the transcription factor nuclear factor erythroid 2-related factor (NRF-2). Combining genetic loss of the NRF-2 repressor Kelch-like ECH-associated protein 1 (Keap1) with lithium treatment revealed that high levels of NRF-2 activation conferred stress resistance, while low levels additionally promoted longevity. The discovery of GSK-3 as a therapeutic target for aging will likely lead to more effective treatments that can modulate mammalian aging and further improve health in later life. PMID:27068460

  3. Lithium Promotes Longevity through GSK3/NRF2-Dependent Hormesis.

    PubMed

    Castillo-Quan, Jorge Iván; Li, Li; Kinghorn, Kerri J; Ivanov, Dobril K; Tain, Luke S; Slack, Cathy; Kerr, Fiona; Nespital, Tobias; Thornton, Janet; Hardy, John; Bjedov, Ivana; Partridge, Linda

    2016-04-19

    The quest to extend healthspan via pharmacological means is becoming increasingly urgent, both from a health and economic perspective. Here we show that lithium, a drug approved for human use, promotes longevity and healthspan. We demonstrate that lithium extends lifespan in female and male Drosophila, when administered throughout adulthood or only later in life. The life-extending mechanism involves the inhibition of glycogen synthase kinase-3 (GSK-3) and activation of the transcription factor nuclear factor erythroid 2-related factor (NRF-2). Combining genetic loss of the NRF-2 repressor Kelch-like ECH-associated protein 1 (Keap1) with lithium treatment revealed that high levels of NRF-2 activation conferred stress resistance, while low levels additionally promoted longevity. The discovery of GSK-3 as a therapeutic target for aging will likely lead to more effective treatments that can modulate mammalian aging and further improve health in later life. PMID:27068460

  4. ERK2 Mediates Metabolic Stress Response to Regulate Cell Fate.

    PubMed

    Shin, Sejeong; Buel, Gwen R; Wolgamott, Laura; Plas, David R; Asara, John M; Blenis, John; Yoon, Sang-Oh

    2015-08-01

    Insufficient nutrients disrupt physiological homeostasis, resulting in diseases and even death. Considering the physiological and pathological consequences of this metabolic stress, the adaptive responses that cells utilize under this condition are of great interest. We show that under low-glucose conditions, cells initiate adaptation followed by apoptosis responses using PERK/Akt and MEK1/ERK2 signaling, respectively. For adaptation, cells engage the ER stress-induced unfolded protein response, which results in PERK/Akt activation and cell survival. Sustained and extreme energetic stress promotes a switch to isoform-specific MEK1/ERK2 signaling, induction of GCN2/eIF2α phosphorylation, and ATF4 expression, which overrides PERK/Akt-mediated adaptation and induces apoptosis through ATF4-dependent expression of pro-apoptotic factors including Bid and Trb3. ERK2 activation during metabolic stress contributes to changes in TCA cycle and amino acid metabolism, and cell death, which is suppressed by glutamate and α-ketoglutarate supplementation. Taken together, our results reveal promising targets to protect cells or tissues from metabolic stress. PMID:26190261

  5. Stress-Regulated Translational Attenuation Adapts Mitochondrial Protein Import Through Tim17A Degradation

    PubMed Central

    Rainbolt, T. Kelly; Atanassova, Neli; Genereux, Joseph C.; Wiseman, R. Luke

    2014-01-01

    SUMMARY Stress-regulated signaling pathways protect mitochondrial proteostasis, and thus mitochondrial function, from pathologic insults. Despite the importance of stress-regulated signaling pathways in mitochondrial proteome maintenance, the molecular mechanisms by which these pathways maintain mitochondrial proteostasis remain largely unknown. Here, we identify Tim17A as a stress-regulated subunit of the Translocase of the Inner Membrane 23 (TIM23) mitochondrial protein import complex. We show that Tim17A protein levels are decreased downstream of stress-regulated translational attenuation induced by eIF2α phosphorylation through a mechanism dependent on the mitochondrial protease YME1L. Furthermore, we demonstrate that decreasing Tim17A protein levels attenuates TIM23-dependent protein import, promotes the induction of mitochondrial Unfolded Protein Response-associated proteostasis genes, and confers stress-resistance in C. elegans and mammalian cells. Thus, our results indicate that Tim17A degradation is a stress-responsive mechanism by which cells adapt mitochondrial protein import efficiency and promote mitochondrial proteostasis in response to the numerous pathologic insults that induce stress-regulated translation attenuation. PMID:24315374

  6. ESTROGEN RECEPTORS AND THE REGULATION OF NEURAL STRESS RESPONSES

    PubMed Central

    Handa, Robert J.; Mani, Shaila K.; Uht, Rosalie M.

    2012-01-01

    It is now well established that estrogens can influence a panoply of physiological and behavioral functions. In many instances, the effects of estrogens are mediated by the ‘classical’ actions of two different estrogen receptors (ER), alpha or beta. Estrogen receptor alpha and beta appear to have opposing actions in the control of stress responses and modulate different neurotransmitter or neuropeptide systems. Studies elucidating the molecular mechanisms for such regulatory processes are currently in progress. Furthermore, the use of ERalpha and ERbeta knockout mouse lines has allowed the exploration of the importance of these receptors in behavioral responses such as anxiety-like and depressive-like behaviors. This review examines some of the recent advances in our knowledge of hormonal control of neuroendocrine and behavioral responses to stress and underscore the importance of these receptors as future therapeutic targets for control of stress-related signaling pathways. PMID:22538291

  7. ABI3 mediates dehydration stress recovery response in Arabidopsis thaliana by regulating expression of downstream genes.

    PubMed

    Bedi, Sonia; Sengupta, Sourabh; Ray, Anagh; Nag Chaudhuri, Ronita

    2016-09-01

    ABI3, originally discovered as a seed-specific transcription factor is now implicated to act beyond seed physiology, especially during abiotic stress. In non-seed plants, ABI3 is known to act in desiccation stress signaling. Here we show that ABI3 plays a role in dehydration stress response in Arabidopsis. ABI3 gene was upregulated during dehydration stress and its expression was maintained during subsequent stress recovery phases. Comparative gene expression studies in response to dehydration stress and stress recovery were done with genes which had potential ABI3 binding sites in their upstream regulatory regions. Such studies showed that several genes including known seed-specific factors like CRUCIFERIN1, CRUCIFERIN3 and LEA-group of genes like LEA76, LEA6, DEHYDRIN LEA and LEA-LIKE got upregulated in an ABI3-dependent manner, especially during the stress recovery phase. ABI3 got recruited to regions upstream to the transcription start site of these genes during dehydration stress response through direct or indirect DNA binding. Interestingly, ABI3 also binds to its own promoter region during such stress signaling. Nucleosomes covering potential ABI3 binding sites in the upstream sequences of the above-mentioned genes alter positions, and show increased H3 K9 acetylation during stress-induced transcription. ABI3 thus mediates dehydration stress signaling in Arabidopsis through regulation of a group of genes that play a role primarily during stress recovery phase. PMID:27457990

  8. Genetics, lifestyle and longevity: Lessons from centenarians

    PubMed Central

    Govindaraju, Diddahally; Atzmon, Gil; Barzilai, Nir

    2015-01-01

    Longevity as a complex life-history trait shares an ontogenetic relationship with other quantitative traits and varies among individuals, families and populations. Heritability estimates of longevity suggest that about a third of the phenotypic variation associated with the trait is attributable to genetic factors, and the rest is influenced by epigenetic and environmental factors. Individuals react differently to the environments that they are a part of, as well as to the environments they construct for their survival and reproduction; the latter phenomenon is known as niche construction. Lifestyle influences longevity at all the stages of development and levels of human diversity. Hence, lifestyle may be viewed as a component of niche construction. Here, we: a) interpret longevity using a combination of genotype-epigenetic-phenotype (GEP) map approach and niche-construction theory, and b) discuss the plausible influence of genetic and epigenetic factors in the distribution and maintenance of longevity among individuals with normal life span on the one hand, and centenarians on the other. Although similar genetic and environmental factors appear to be common to both of these groups, exceptional longevity may be influenced by polymorphisms in specific genes, coupled with superior genomic stability and homeostatic mechanisms, maintained by negative frequency-dependent selection. We suggest that a comparative analysis of longevity between individuals with normal life span and centenarians, along with insights from population ecology and evolutionary biology, would not only advance our knowledge of biological mechanisms underlying human longevity, but also provide deeper insights into extending healthy life span. PMID:26937346

  9. Regulation of Adult Neurogenesis and Plasticity by (Early) Stress, Glucocorticoids, and Inflammation.

    PubMed

    Lucassen, Paul J; Oomen, Charlotte A; Naninck, Eva F G; Fitzsimons, Carlos P; van Dam, Anne-Marie; Czeh, Boldizsár; Korosi, Aniko

    2015-09-01

    Exposure to stress is one of the best-known negative regulators of adult neurogenesis (AN). We discuss changes in neurogenesis in relation to exposure to stress, glucocorticoid hormones, and inflammation, with a particular focus on early development and on lasting effects of stress. Although the effects of acute and mild stress on AN are generally brief and can be quickly overcome, chronic exposure or more severe forms of stress can induce longer lasting reductions in neurogenesis that can, however, in part, be overcome by subsequent exposure to exercise, drugs targeting the stress system, and some antidepressants. Exposure to stress, particularly during the sensitive period of early life, may (re)program brain plasticity, in particular, in the hippocampus. This may increase the risk to develop cognitive or anxiety symptoms, common to brain diseases like dementia and depression in which plasticity changes occur, and a normalization of neurogenesis may be required for a successful treatment response and recovery. PMID:26330520

  10. Genome-Wide Scan Informed by Age-Related Disease Identifies Loci for Exceptional Human Longevity

    PubMed Central

    Fortney, Kristen; Dobriban, Edgar; Garagnani, Paolo; Pirazzini, Chiara; Monti, Daniela; Mari, Daniela; Atzmon, Gil; Barzilai, Nir; Franceschi, Claudio; Owen, Art B.; Kim, Stuart K.

    2015-01-01

    We developed a new statistical framework to find genetic variants associated with extreme longevity. The method, informed GWAS (iGWAS), takes advantage of knowledge from large studies of age-related disease in order to narrow the search for SNPs associated with longevity. To gain support for our approach, we first show there is an overlap between loci involved in disease and loci associated with extreme longevity. These results indicate that several disease variants may be depleted in centenarians versus the general population. Next, we used iGWAS to harness information from 14 meta-analyses of disease and trait GWAS to identify longevity loci in two studies of long-lived humans. In a standard GWAS analysis, only one locus in these studies is significant (APOE/TOMM40) when controlling the false discovery rate (FDR) at 10%. With iGWAS, we identify eight genetic loci to associate significantly with exceptional human longevity at FDR < 10%. We followed up the eight lead SNPs in independent cohorts, and found replication evidence of four loci and suggestive evidence for one more with exceptional longevity. The loci that replicated (FDR < 5%) included APOE/TOMM40 (associated with Alzheimer’s disease), CDKN2B/ANRIL (implicated in the regulation of cellular senescence), ABO (tags the O blood group), and SH2B3/ATXN2 (a signaling gene that extends lifespan in Drosophila and a gene involved in neurological disease). Our results implicate new loci in longevity and reveal a genetic overlap between longevity and age-related diseases and traits, including coronary artery disease and Alzheimer’s disease. iGWAS provides a new analytical strategy for uncovering SNPs that influence extreme longevity, and can be applied more broadly to boost power in other studies of complex phenotypes. PMID:26677855

  11. Protein kinase FgSch9 serves as a mediator of the target of rapamycin and high osmolarity glycerol pathways and regulates multiple stress responses and secondary metabolism in Fusarium graminearum.

    PubMed

    Gu, Qin; Zhang, Chengqi; Yu, Fangwei; Yin, Yanni; Shim, Won-Bo; Ma, Zhonghua

    2015-08-01

    Saccharomyces cerevisiae protein kinase Sch9 is one of the downstream effectors of the target of rapamycin (TOR) complex 1 and plays multiple roles in stress resistance, longevity and nutrient sensing. However, the functions of Sch9 orthologs in filamentous fungi, particularly in pathogenic species, have not been characterized to date. Here, we investigated biological and genetic functions of FgSch9 in Fusarium graminearum. The FgSCH9 deletion mutant (ΔFgSch9) was defective in aerial hyphal growth, hyphal branching and conidial germination. The mutant exhibited increased sensitivity to osmotic and oxidative stresses, cell wall-damaging agents, and to rapamycin, while showing increased thermal tolerance. We identified FgMaf1 as one of the FgSch9-interacting proteins that plays an important role in regulating mycotoxin biosynthesis and virulence of F. graminearum. Co-immunoprecipitation and affinity capture-mass spectrometry assays showed that FgSch9 also interacts with FgTor and FgHog1. More importantly, both ΔFgSch9 and FgHog1 null mutant (ΔFgHog1) exhibited increased sensitivity to osmotic and oxidative stresses. This defect was more severe in the FgSch9/FgHog1 double mutant. Taken together, we propose that FgSch9 serves as a mediator of the TOR and high osmolarity glycerol pathways, and regulates vegetative differentiation, multiple stress responses and secondary metabolism in F. graminearum. PMID:24903410

  12. Histone deacetylase HDA9 negatively regulates salt and drought stress responsiveness in Arabidopsis.

    PubMed

    Zheng, Yu; Ding, Yue; Sun, Xuan; Xie, Sisi; Wang, Dan; Liu, Xiaoyun; Su, Lufang; Wei, Wei; Pan, Lei; Zhou, Dao-Xiu

    2016-04-01

    Histone modification is an important epigenetic regulation in higher plants adapting to environment changes including salt and drought stresses. In this report, we show that the Arabidopsis RPD3-type histone deacetylase HDA9 is involved in modulating plant responses to salt and drought stresses in Arabidopsis. Loss-of-function mutants of the gene displayed phenotypes (such as seedling root growth and seed germination) insensitive to NaCl and polyethylene glycol (PEG) treatments. HDA9 mutation led to up-regulation of many genes, among which those involved in response to water deprivation stress (GO: 0009414) were enriched. These genes were much more induced in the mutants than wild-type plants when treated with PEG and NaCl. In addition, we found that in the mutants, salt and drought stresses led to much higher levels of histone H3K9 acetylation at promoters of 14 genes randomly selected from those that respond to water-deprivation stress than in wild-type plants. Our study suggested that HDA9 might be a novel chromatin protein that negatively regulates plant sensitivity to salt and drought stresses by regulating histone acetylation levels of a large number of stress-responsive genes in Arabidopsis. PMID:26733691

  13. Transcriptional profiling of Petunia seedlings reveals candidate regulators of the cold stress response

    PubMed Central

    Li, Bei; Ning, Luyun; Zhang, Junwei; Bao, Manzhu; Zhang, Wei

    2015-01-01

    Petunias are important ornamentals with the capacity for cold acclimation. So far, there is limited information concerning gene regulation and signaling pathways associated with the cold stress response in petunias. A custom-designed petunia microarray representing 24816 genes was used to perform transcriptome profiling in petunia seedlings subjected to cold at 2°C for 0.5 h, 2 h, 24 h, and 5 d. A total of 2071 transcripts displayed differential expression patterns under cold stress, of which 1149 were up-regulated and 922 were down-regulated. Gene ontology enrichment analysis demarcated related biological processes, suggesting a possible link between flavonoid metabolism and plant adaptation to low temperatures. Many novel stress-responsive regulators were revealed, suggesting that diverse regulatory pathways may exist in petunias in addition to the well-characterized CBF pathway. The expression changes of selected genes under cold and other abiotic stress conditions were confirmed by real-time RT-PCR. Furthermore, weighted gene co-expression network analysis divided the petunia genes on the array into 65 modules that showed high co-expression and identified stress-specific hub genes with high connectivity. Our identification of these transcriptional responses and groups of differentially expressed regulators will facilitate the functional dissection of the molecular mechanism in petunias responding to environment stresses and extend our ability to improve cold tolerance in plants. PMID:25784921

  14. Natural antisense transcripts regulate the neuronal stress response and excitability

    PubMed Central

    Zheng, Xingguo; Valakh, Vera; DiAntonio, Aaron; Ben-Shahar, Yehuda

    2014-01-01

    Neurons regulate ionic fluxes across their plasma membrane to maintain their excitable properties under varying environmental conditions. However, the mechanisms that regulate ion channels abundance remain poorly understood. Here we show that pickpocket 29 (ppk29), a gene that encodes a Drosophila degenerin/epithelial sodium channel (DEG/ENaC), regulates neuronal excitability via a protein-independent mechanism. We demonstrate that the mRNA 3′UTR of ppk29 affects neuronal firing rates and associated heat-induced seizures by acting as a natural antisense transcript (NAT) that regulates the neuronal mRNA levels of seizure (sei), the Drosophila homolog of the human Ether-à-go-go Related Gene (hERG) potassium channel. We find that the regulatory impact of ppk29 mRNA on sei is independent of the sodium channel it encodes. Thus, our studies reveal a novel mRNA dependent mechanism for the regulation of neuronal excitability that is independent of protein-coding capacity. DOI: http://dx.doi.org/10.7554/eLife.01849.001 PMID:24642409

  15. Redefining neuroendocrinology: stress, sex and cognitive and emotional regulation

    PubMed Central

    McEwen, Bruce S.; Gray, Jason D.; Nasca, Carla

    2015-01-01

    The discovery of steroid hormone receptors in brain regions that mediate every aspect of brain function has broadened the definition of “neuroendocrinology” to include the reciprocal communication between the brain and the body via hormonal and neural pathways. The brain is the central organ of stress and adaptation to stress because it perceives and determines what is threatening, as well as the behavioral and physiological responses to the stressor. The adult and developing brain possess remarkable structural and functional plasticity in response to stress, including neuronal replacement, dendritic remodeling, and synapse turnover. Stress causes an imbalance of neural circuitry subserving cognition, decision-making, anxiety and mood that can alter expression of those behaviors and behavioral states. This imbalance, in turn, affects systemic physiology via neuroendocrine, autonomic, immune and metabolic mediators. In the short term, as for increased fearful vigilance and anxiety in a threatening environment, these changes may be adaptive. But, if the danger passes and the behavioral state persists along with the changes in neural circuitry, such maladaptation may need intervention with a combination of pharmacological and behavioral therapies, as is the case for chronic anxiety and depression. There are important sex differences in the brain responses to stressors that are in urgent need of further exploration. Moreover, adverse early-life experience, interacting with alleles of certain genes, produce lasting effects on brain and body over the life-course via epigenetic mechanisms. While prevention is most important, the plasticity of the brain gives hope for therapies that take into consideration brain-body interactions. PMID:25934706

  16. Transcriptional regulation of gene expression during osmotic stress responses by the mammalian target of rapamycin.

    PubMed

    Ortells, M Carmen; Morancho, Beatriz; Drews-Elger, Katherine; Viollet, Benoit; Laderoute, Keith R; López-Rodríguez, Cristina; Aramburu, Jose

    2012-05-01

    Although stress can suppress growth and proliferation, cells can induce adaptive responses that allow them to maintain these functions under stress. While numerous studies have focused on the inhibitory effects of stress on cell growth, less is known on how growth-promoting pathways influence stress responses. We have approached this question by analyzing the effect of mammalian target of rapamycin (mTOR), a central growth controller, on the osmotic stress response. Our results showed that mammalian cells exposed to moderate hypertonicity maintained active mTOR, which was required to sustain their cell size and proliferative capacity. Moreover, mTOR regulated the induction of diverse osmostress response genes, including targets of the tonicity-responsive transcription factor NFAT5 as well as NFAT5-independent genes. Genes sensitive to mTOR-included regulators of stress responses, growth and proliferation. Among them, we identified REDD1 and REDD2, which had been previously characterized as mTOR inhibitors in other stress contexts. We observed that mTOR facilitated transcription-permissive conditions for several osmoresponsive genes by enhancing histone H4 acetylation and the recruitment of RNA polymerase II. Altogether, these results reveal a previously unappreciated role of mTOR in regulating transcriptional mechanisms that control gene expression during cellular stress responses. PMID:22287635

  17. Sympathetic regulation during thermal stress in human aging and disease.

    PubMed

    Greaney, Jody L; Kenney, W Larry; Alexander, Lacy M

    2016-04-01

    Humans control their core temperature within a narrow range via precise adjustments of the autonomic nervous system. In response to changing core and/or skin temperature, several critical thermoregulatory reflex effector responses are initiated and include shivering, sweating, and changes in cutaneous blood flow. Cutaneous vasomotor adjustments, mediated by modulations in sympathetic nerve activity (SNA), aid in the maintenance of thermal homeostasis during cold and heat stress since (1) they serve as the first line of defense of body temperature and are initiated before other thermoregulatory effectors, and (2) they are on the efferent arm of non-thermoregulatory reflex systems, aiding in the maintenance of blood pressure and organ perfusion. This review article highlights the sympathetic responses of humans to thermal stress, with a specific focus on primary aging as well as impairments that occur in both heart disease and type 2 diabetes mellitus. Age- and pathology-related changes in efferent muscle and skin SNA during cold and heat stress, measured directly in humans using microneurography, are discussed. PMID:26627337

  18. Mechanical Stress Regulation of Plant Growth and Development

    NASA Technical Reports Server (NTRS)

    Mitchell, C. A.

    1985-01-01

    Growth dynamics analysis was used to determine to what extent the seismic stress induced reduction in photosynthetic productivity in shaken soybeans was due to less photosynthetic surface, and to what extent to lower efficiency of assimulation. Seismic stress reduces shoot transpiration rate 17% and 15% during the first and second 45 minute periods following a given treatment. Shaken plants also had a 36% greater leaf water potential 30 minutes after treatment. Continuous measurement of whole plant photosynthetic rate shows that a decline in CO2 fixation began within seconds after the onset of shaking treatment and continued to decline to 16% less than that of controls 20 minutes after shaking, after which gradual recovery of photosynthesis begins. Photosynthetic assimilation recovered completely before the next treatment 5 hours later. The transitory decrease in photosynthetic rate was due entirely to a two fold increase in stomatal resistance to CO2 by the abaxial leaf surface. Mesophyll resistance was not significantly affected by periodic seismic treatment. Temporary stomatal aperture reduction and decreased CO2 fixation are responsible for the lower dry weight of seismic stressed plants growing in a controlled environment.

  19. Redox-dependent regulation, redox control and oxidative damage in plant cells subjected to abiotic stress.

    PubMed

    Dietz, Karl-Josef

    2010-01-01

    Stress development intricately involves uncontrolled redox reactions and oxidative damage to functional macromolecules. Three phases characterize progressing abiotic stress and the stress strength; in the first phase redox-dependent deregulation in metabolism, in the second phase detectable development of oxidative damage and in the third phase cell death. Each phase is characterized by traceable biochemical features and specific molecular responses that reflect on the one hand cell damage but on the other hand indicate specific regulation and redox signalling aiming at compensation of stress impact. PMID:20387040

  20. Stress and corticosteroids regulate rat hippocampal mitochondrial DNA gene expression via the glucocorticoid receptor.

    PubMed

    Hunter, Richard G; Seligsohn, Ma'ayan; Rubin, Todd G; Griffiths, Brian B; Ozdemir, Yildirim; Pfaff, Donald W; Datson, Nicole A; McEwen, Bruce S

    2016-08-01

    Glucocorticoids (GCs) are involved in stress and circadian regulation, and produce many actions via the GC receptor (GR), which is classically understood to function as a nuclear transcription factor. However, the nuclear genome is not the only genome in eukaryotic cells. The mitochondria also contain a small circular genome, the mitochondrial DNA (mtDNA), that encodes 13 polypeptides. Recent work has established that, in the brain and other systems, the GR is translocated from the cytosol to the mitochondria and that stress and corticosteroids have a direct influence on mtDNA transcription and mitochondrial physiology. To determine if stress affects mitochondrially transcribed mRNA (mtRNA) expression, we exposed adult male rats to both acute and chronic immobilization stress and examined mtRNA expression using quantitative RT-PCR. We found that acute stress had a main effect on mtRNA expression and that expression of NADH dehydrogenase 1, 3, and 6 (ND-1, ND-3, ND-6) and ATP synthase 6 (ATP-6) genes was significantly down-regulated. Chronic stress induced a significant up-regulation of ND-6 expression. Adrenalectomy abolished acute stress-induced mtRNA regulation, demonstrating GC dependence. ChIP sequencing of GR showed that corticosterone treatment induced a dose-dependent association of the GR with the control region of the mitochondrial genome. These findings demonstrate GR and stress-dependent transcriptional regulation of the mitochondrial genome in vivo and are consistent with previous work linking stress and GCs with changes in the function of brain mitochondria. PMID:27457949

  1. The moderator role of emotion regulation ability in the link between stress and well-being

    PubMed Central

    Extremera, Natalio; Rey, Lourdes

    2015-01-01

    This article examined the moderating role of a central core dimension of emotional intelligence—emotion-regulation ability—in the relationship between perceived stress and indicators of well-being (depression and subjective happiness) in a sample from a community adult population. The relationships for males and females on these dimensions were also compared. Results revealed that emotion-regulation abilities moderated both the association between perceived stress and depression/happiness for the total sample. However, a gender-specific analysis showed that the moderation effect was only significant for males. In short, when males reported a high level of perceived stress, those with high scores in regulating emotions reported higher scores in subjective happiness and lower depression symptoms than those with low regulating emotions. However, no interaction effect of regulating emotions and stress for predicting subjective happiness and depression was found for females. In developing stress management programmes for reducing depression and increasing well-being, these findings suggest that training in emotional regulation may be more beneficial for males than females. Our findings are discussed in terms of the need for future research to understand the different gender associations and to consider these differences in further intervention programmes. PMID:26579017

  2. The moderator role of emotion regulation ability in the link between stress and well-being.

    PubMed

    Extremera, Natalio; Rey, Lourdes

    2015-01-01

    This article examined the moderating role of a central core dimension of emotional intelligence-emotion-regulation ability-in the relationship between perceived stress and indicators of well-being (depression and subjective happiness) in a sample from a community adult population. The relationships for males and females on these dimensions were also compared. Results revealed that emotion-regulation abilities moderated both the association between perceived stress and depression/happiness for the total sample. However, a gender-specific analysis showed that the moderation effect was only significant for males. In short, when males reported a high level of perceived stress, those with high scores in regulating emotions reported higher scores in subjective happiness and lower depression symptoms than those with low regulating emotions. However, no interaction effect of regulating emotions and stress for predicting subjective happiness and depression was found for females. In developing stress management programmes for reducing depression and increasing well-being, these findings suggest that training in emotional regulation may be more beneficial for males than females. Our findings are discussed in terms of the need for future research to understand the different gender associations and to consider these differences in further intervention programmes. PMID:26579017

  3. The behavior of renal-regulating hormones during hypogravic stress

    NASA Technical Reports Server (NTRS)

    Leonard, J. I.

    1985-01-01

    The regulation of fluid and electrolyte behavior during space flight is believed to be under control, in large part, of a group of hormones which have their major effects on renal excretion. The hormones studied include renin-angitensin, aldosterone, and antidiuretic hormone (ADH). The regulatory systems of these renal-regulating hormones as they act individually and in concert with each other are analyzed. The analysis is based on simulations of the mathematical model of Guyton. A generalized theory is described which accounts for both short-term and long-term behavior of this set of hormones.

  4. The Redox-Sensitive Chloroplast Trehalose-6-Phosphate Phosphatase AtTPPD Regulates Salt Stress Tolerance

    PubMed Central

    Krasensky, Julia; Broyart, Caroline; Rabanal, Fernando A.

    2014-01-01

    Abstract Aims: High salinity stress impairs plant growth and development. Trehalose metabolism has been implicated in sugar signaling, and enhanced trehalose metabolism can positively regulate abiotic stress tolerance. However, the molecular mechanism(s) of the stress-related trehalose pathway and the role of individual trehalose biosynthetic enzymes for stress tolerance remain unclear. Results: Trehalose-6-phosphate phosphatase (TPP) catalyzes the final step of trehalose metabolism. Investigating the subcellular localization of the Arabidopsis thaliana TPP family members, we identified AtTPPD as a chloroplast-localized enzyme. Plants deficient in AtTPPD were hypersensitive, whereas plants overexpressing AtTPPD were more tolerant to high salinity stress. Elevated stress tolerance of AtTPPD overexpressors correlated with high starch levels and increased accumulation of soluble sugars, suggesting a role for AtTPPD in regulating sugar metabolism under salinity conditions. Biochemical analyses indicate that AtTPPD is a target of post-translational redox regulation and can be reversibly inactivated by oxidizing conditions. Two cysteine residues were identified as the redox-sensitive sites. Structural and mutation analyses suggest that the formation of an intramolecular disulfide bridge regulates AtTPPD activity. Innovation: The activity of different AtTPP isoforms, located in the cytosol, nucleus, and chloroplasts, can be redox regulated, suggesting that the trehalose metabolism might relay the redox status of different cellular compartments to regulate diverse biological processes such as stress responses. Conclusion: The evolutionary conservation of the two redox regulatory cysteine residues of TPPs in spermatophytes indicates that redox regulation of TPPs might be a common mechanism enabling plants to rapidly adjust trehalose metabolism to the prevailing environmental and developmental conditions. Antioxid. Redox Signal. 21, 1289–1304. PMID:24800789

  5. Biotic Stress Globally Down-Regulates Photosynthesis Genes

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Upon herbivore and pathogen attacks, plants switch from processes supporting growth and reproduction to defense by inducing a set of defense genes and down-regulating most of the nuclear encoded photosynthetic genes. To determine if this transcriptional response is universal we used transcriptome da...

  6. Energetics and longevity in birds

    PubMed Central

    Furness, L. J.

    2008-01-01

    The links between energy expenditure and ageing are different at different levels of enquiry. When studies have examined the relationships between different species within a given class the association is generally negative—animals with greater metabolism per gram of tissue live shorter lives. Within species, or between classes (e.g. between birds and mammals) the association is the opposite—animals with higher metabolic rates live longer. We have previously shown in mammals that the negative association between lifespan and metabolic rate is in fact an artefact of using resting rather than daily energy expenditure, and of failing to adequately take into account the confounding effects of body size and the lack of phylogenetic independence of species data. When these factors are accounted for, across species of mammals, the ones with higher metabolism also have the largest lifetime expenditures of energy—consistent with the inter-class and intra-specific data. A previous analysis in birds did not yield the same pattern, but this may have been due to a lack of sufficient power in the analysis. Here we present an analysis of a much enlarged data set (>300 species) for metabolic and longevity traits in birds. These data show very similar patterns to those in mammals. Larger individuals have longer lives and lower per-gram resting and daily energy expenditures, hence there is a strong negative relationship between longevity and mass-specific metabolism. This relationship disappears when the confounding effects of body mass and phylogeny are accounted for. Across species of birds, lifetime expenditure of energy per gram of tissue based on both daily and resting energy expenditure is positively related to metabolic intensity, mirroring these statistical relationships in mammals and synergising with the positive associations of metabolism with lifespan within species and between vertebrate classes. PMID:19424858

  7. Lifelong pathways to longevity: personality, relationships, flourishing, and health.

    PubMed

    Kern, Margaret L; Della Porta, Serenity S; Friedman, Howard S

    2014-12-01

    Building upon decades of research with the lifelong (nine-decade) Terman Life Cycle Study, we present a life pathway model for understanding human thriving that accounts for long-term individual difference in health and longevity, with a particular focus on child personality and adult social relationships. Developing data derived and supplemented from the Terman study (N = 570 males, 451 females), we employed regression and survival analyses to test models of childhood personality predicting adult psychosocial factors (subjective well-being, family relationships, community involvement, subjective achievement, hardships) and subsequent longevity. Child personality differentially related to midlife social relationships, well-being, and hardships. Conscientiousness and good social relationships predicted longer life, whereas subjective well-being was unrelated to mortality risk. Examining multiple life factors across long time periods uncovers important pathways through which personality relates to premature mortality or longevity. Typical stress-and-illness models are untenable and should be replaced with life span trajectory approaches. PMID:23927423

  8. Neural models on temperature regulation for cold-stressed animals

    NASA Technical Reports Server (NTRS)

    Horowitz, J. M.

    1975-01-01

    The present review evaluates several assumptions common to a variety of current models for thermoregulation in cold-stressed animals. Three areas covered by the models are discussed: signals to and from the central nervous system (CNS), portions of the CNS involved, and the arrangement of neurons within networks. Assumptions in each of these categories are considered. The evaluation of the models is based on the experimental foundations of the assumptions. Regions of the nervous system concerned here include the hypothalamus, the skin, the spinal cord, the hippocampus, and the septal area of the brain.

  9. Membrane regulation of the stress response from prokaryotic models to mammalian cells.

    PubMed

    Vigh, Laszlo; Nakamoto, Hitoshi; Landry, Jacques; Gomez-Munoz, Antonio; Harwood, John L; Horvath, Ibolya

    2007-10-01

    "Membrane regulation" of stress responses in various systems is widely studied. In poikilotherms, membrane rigidification could be the first reaction to cold perception: reducing membrane fluidity of membranes at physiological temperatures is coupled with enhanced cold inducibility of a number of genes, including desaturases (see J.L. Harwood's article in this Proceedings volume). A similar role of changes in membrane physical state in heat (oxidative stress, etc.) sensing- and signaling gained support recently from prokaryotes to mammalian cells. Stress-induced remodeling of membrane lipids could influence generation, transduction, and deactivation of stress signals, either through global effects on the fluidity of the membrane matrix, or by specific interactions of boundary (or raft) lipids with receptor proteins, lipases, ion channels, etc. Our data point to membranes not only as targets of stress, but also as sensors in activating a stress response. PMID:17656573

  10. 78 FR 78694 - Orders: Supplemental Orders on Reporting by Regulated Entities of Stress Testing Results as of...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-12-27

    ... AGENCY 12 CFR Part 1238 Orders: Supplemental Orders on Reporting by Regulated Entities of Stress Testing... additional appendices of scenario assumptions to be used for stress testing. II. Orders For the convenience... 2013-OR-FHLMC-3 SUPPLEMENTAL ORDER ON REPORTING BY REGULATED ENTITIES OF STRESS TESTING RESULTS AS...

  11. Distribution of the longevity gene product, SIRT1, in developing mouse organs.

    PubMed

    Ogawa, Tetsuo; Wakai, Chizu; Saito, Tomomi; Murayama, Aya; Mimura, Yuuichi; Youfu, Sachiko; Nakamachi, Tomoya; Kuwagata, Makiko; Satoh, Kazue; Shioda, Seiji

    2011-06-01

    A longevity gene product, Sir2 (silent information regulator 2) is a NAD-dependent histone deacetylase involved in longevity in yeasts, worms and flies. The mammalian homolog of Sir2, SIRT1(sirtuin 1), has been shown to play important roles related to anti-aging effects (regulating apoptosis, stress tolerance, insulin resistance, and fat metabolism). Recently, SIRT1 expression has been demonstrated to occur at as early as embryonic day 10.5 in mice. SIRT1 during developing period may be involved in the mechanism of developmental origins of adult diseases, such as diabetes and cardiovascular disease. To investigate the contribution of SIRT1, it is important to reveal the distribution of this protein during development. In the present study, we demonstrated the distribution of immunoreactivity of SIRT1 in mouse organs during prenatal and neonatal development by staining a wide variety of serial sections. The SIRT1 immunoreactivity was strongly observed in the neuroepithelial layer, dorsal root ganglion, trigeminal ganglion, eyes, roots of whiskers, and internal organs, including the testis, liver, heart, kidney, and lung during the fetal period. Neurons which had finished migrating still showed relatively strong immunoreactivity. The immunoreactivity was completely absorbed by the blocking peptide in an absorption test. During the postnatal period, the immunoreactivities in most of these organs, except the heart and testis weakened, with the liver most dramatically affected. As SIRT1 expression was demonstrated in a wide variety of developing organs, further study to investigate prenatal factors which affect SIRT1 expression and its activity is important. PMID:21054562

  12. Regulation of grain yield in rice under well-watered and drought stress conditions by GUDK

    PubMed Central

    Ramegowda, Venkategowda; Basu, Supratim; Gupta, Chirag; Pereira, Andy

    2015-01-01

    Increasing the grain yield of cereals, which is stable under unfavorable environmental stress, is a major objective to sustain production and feed the growing world population. Recently, we functionally characterized a receptor-like cytoplasmic kinase, named GROWTH UNDER DROUGHT KINASE (GUDK), revealing its role in regulating grain yield under well-watered and drought stress conditions by transphosphorylating the OsAP37 transcription factor. GUDK is induced under several stresses and its loss-of-function increased the sensitivity of rice seedlings to salinity, osmotic stress, and abscisic acid treatment. In addition to reduced tolerance of gudk mutant plants to drought stress at vegetative stage, a significant reduction in grain yield was observed under well-watered and drought stress conditions at reproductive stage. Gene co-expression analysis supports the role of GUDK in regulating important biological processes both under control and stress conditions. Thus, our results suggest that GUDK has the potential to regulate grain yield both under favorable and unfavorable conditions. PMID:26633564

  13. Reversible glutathionylation of Sir2 by monothiol glutaredoxins Grx3/4 regulates stress resistance.

    PubMed

    Vall-Llaura, Núria; Reverter-Branchat, Gemma; Vived, Celia; Weertman, Naomi; Rodríguez-Colman, María José; Cabiscol, Elisa

    2016-07-01

    The regulatory mechanisms of yeast Sir2, the founding member of the sirtuin family involved in oxidative stress and aging, are unknown. Redox signaling controls many cellular functions, especially under stress situations, with dithiol glutaredoxins (Grxs) playing an important role. However, monothiol Grxs are not considered to have major oxidoreductase activity. The present study investigated the redox regulation of yeast Sir2, together with the role and physiological impact of monothiol Grx3/4 as Sir2 thiol-reductases upon stress. S-glutathionylation of Sir2 upon disulfide stress was demonstrated both in vitro and in vivo, and decreased Sir2 deacetylase activity. Physiological levels of nuclear Grx3/4 can reverse the observed post-translational modification. Grx3/4 interacted with Sir2 and reduced it after stress, thereby restoring telomeric silencing activity. Using site-directed mutagenesis, key cysteine residues at the catalytic domain of Sir2 were identified as a target of S-glutathionylation. Mutation of these residues resulted in cells with increased resistance to disulfide stress. We provide new mechanistic insights into Grx3/4 regulation of Sir2 by S-deglutathionylation to increase cell resistance to stress. This finding offers news perspectives on monothiol Grxs in redox signaling, describing Sir2 as a physiological substrate regulated by S-glutathionylation. These results might have a relevant role in understanding aging and age-related diseases. PMID:27085841

  14. Transcription factor WRKY46 regulates osmotic stress responses and stomatal movement independently in Arabidopsis.

    PubMed

    Ding, Zhong Jie; Yan, Jing Ying; Xu, Xiao Yan; Yu, Di Qiu; Li, Gui Xin; Zhang, Shu Qun; Zheng, Shao Jian

    2014-07-01

    Drought and salt stress severely inhibit plant growth and development; however, the regulatory mechanisms of plants in response to these stresses are not fully understood. Here we report that the expression of a WRKY transcription factor WRKY46 is rapidly induced by drought, salt and oxidative stresses. T-DNA insertion of WRKY46 leads to more sensitivity to drought and salt stress, whereas overexpression of WRKY46 (OV46) results in hypersensitivity in soil-grown plants, with a higher water loss rate, but with increased tolerance on the sealed agar plates. Stomatal closing in the OV46 line is insensitive to ABA because of a reduced accumulation of reactive oxygen species (ROS) in the guard cells. We further find that WRKY46 is expressed in guard cells, where its expression is not affected by dehydration, and is involved in light-dependent stomatal opening. Microarray analysis reveals that WRKY46 regulates a set of genes involved in cellular osmoprotection and redox homeostasis under dehydration stress, which is confirmed by ROS and malondialdehyde (MDA) levels in stressed seedlings. Moreover, WRKY46 modulates light-dependent starch metabolism in guard cells via regulating QUA-QUINE STARCH (QQS) gene expression. Taken together, we demonstrate that WRKY46 plays dual roles in regulating plant responses to drought and salt stress and light-dependent stomatal opening in guard cells. PMID:24773321

  15. Identification of genes regulated by chronic psychosocial stress and antidepressant treatment in the hippocampus.

    PubMed

    Alfonso, Julieta; Pollevick, Guido D; Van Der Hart, Marieke G; Flügge, Gabriele; Fuchs, Eberhard; Frasch, Alberto C C

    2004-02-01

    Analysis of differentially expressed genes in the brain is a promising tool for elucidating pathological mechanisms that lead to central nervous disorders. Stress is known to be involved in the development of psychopathologies such as depression. In the present study, we searched for differentially expressed genes in the hippocampal formation after chronic psychosocial stress and after treatment with the antidepressant clomipramine. Experiments were conducted in male tree shrews, a valid psychosocial stress model in which antidepressant drugs prevent diverse effects of stress. Because many effects of stress have been attributed to the stress-induced elevation in glucocorticoids, we screened two subtractive hippocampal cDNA libraries generated from RNA of chronic cortisol-treated animals. Using real-time PCR to measure mRNA amounts, we identified five sequences whose expression levels differed between stressed animals and controls. Transcript levels of four of them, nerve growth factor (NGF), membrane glycoprotein 6a (M6a), CDC-like kinase 1 (CLK-1) and G-protein alpha q (GNAQ) were reduced by chronic psychosocial stress. Reduced amounts of these genes, which are all related to processes of cell differentiation, is in agreement with previous findings showing a retraction of dendrites and an impairment of neurogenesis in the hippocampal formation after chronic stress. An additional expressed sequence that was also regulated by stress could not be assigned to any known gene. Treatment with the antidepressant clomipramine prevented stress effects on expression of M6a, CLK-1, GNAQ and the novel sequence, but showed no effect on NGF stress-induced down-regulation. These findings support the concept that depressive disorders are accompanied by processes of neuronal dedifferentiation, at least in the hippocampal formation, and that antidepressants prevent these processes. PMID:14984416

  16. Drosophila melanogaster Activating Transcription Factor 4 Regulates Glycolysis During Endoplasmic Reticulum Stress

    PubMed Central

    Lee, Ji Eun; Oney, McKenna; Frizzell, Kimberly; Phadnis, Nitin; Hollien, Julie

    2015-01-01

    Endoplasmic reticulum (ER) stress results from an imbalance between the load of proteins entering the secretory pathway and the ability of the ER to fold and process them. The response to ER stress is mediated by a collection of signaling pathways termed the unfolded protein response, which plays important roles in development and disease. Here we show that in Drosophila melanogaster S2 cells, ER stress induces a coordinated change in the expression of genes involved in carbon metabolism. Genes encoding enzymes that carry out glycolysis were up-regulated, whereas genes encoding proteins in the tricarboxylic acid cycle and respiratory chain complexes were down-regulated. The unfolded protein response transcription factor Atf4 was necessary for the up-regulation of glycolytic enzymes and Lactate dehydrogenase (Ldh). Furthermore, Atf4 binding motifs in promoters for these genes could partially account for their regulation during ER stress. Finally, flies up-regulated Ldh and produced more lactate when subjected to ER stress. Together, these results suggest that Atf4 mediates a shift from a metabolism based on oxidative phosphorylation to one more heavily reliant on glycolysis, reminiscent of aerobic glycolysis or the Warburg effect observed in cancer and other proliferative cells. PMID:25681259

  17. Fluid shear stress regulates metalloproteinase-1 and 2 in human periodontal ligament cells: involvement of extracellular signal-regulated kinase (ERK) and P38 signaling pathways.

    PubMed

    Zheng, Lisha; Huang, Yan; Song, Wei; Gong, Xianghui; Liu, Meili; Jia, Xiaolin; Zhou, Gang; Chen, Luoping; Li, Ang; Fan, Yubo

    2012-09-21

    Matrix metalloproteinase (MMP)-1, 2, with their endogenous inhibitors, tissue inhibitor of metalloproteinase (TIMP)-1, 2 are critical for extracellular matrix remodeling in human periodontal ligament (PDL) and their expression are sensitive to mechanical stresses. Shear stress as the main type of mechanical stress in tooth movement is involved in matrix turnover. However, how shear stress regulates MMPs and TIMPs system is still unclear. In this study, we investigated the effect of fluid shear stress on expression of MMP-1, 2 and TIMP-1, 2 in human PDL cells and the possible roles of mitogen-activated protein kinases in this process. Three levels of fluid shear stresses (6, 9 and 12 dyn/cm(2)) were loaded on PDL cells for 2, 4, 8 and 12h. The results indicated that fluid shear stress rearranged cytoskeleton in PDL cells. Fluid shear stress increased expression of MMP-1, 2, TIMP-1 and suppressed TIMP-2 expression. MAP kinases including extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 were activated rapidly by fluid shear stress. The ERK inhibitor blocked fluid shear stress induced MMP-1 expression and P38 inhibitor reduced fluid shear stress stimulated MMP-2 expression. Our study suggested that fluid shear stress involved in PDL remodeling via regulating MMP-1, 2 and TIMP-1, 2 expression. ERK regulated fluid shear stress induced MMP-1 expression and P38 play a role in fluid shear stress induced MMP-2 upregulation. PMID:22863019

  18. An RNA chaperone, AtCSP2, negatively regulates salt stress tolerance

    PubMed Central

    Sasaki, Kentaro; Liu, Yuelin; Kim, Myung-Hee; Imai, Ryozo

    2015-01-01

    Cold shock domain (CSD) proteins are RNA chaperones that destabilize RNA secondary structures. Arabidopsis Cold Shock Domain Protein 2 (AtCSP2), one of the 4 CSD proteins (AtCSP1-AtCSP4) in Arabidopsis, is induced during cold acclimation but negatively regulates freezing tolerance. Here, we analyzed the function of AtCSP2 in salt stress tolerance. A double mutant, with reduced AtCSP2 and no AtCSP4 expression (atcsp2–3 atcsp4–1), displayed higher survival rates after salt stress. In addition, overexpression of AtCSP2 resulted in reduced salt stress tolerance. These data demonstrate that AtCSP2 acts as a negative regulator of salt stress tolerance in Arabidopsis. PMID:26252779

  19. Determinants of Frailty and Longevity: Are They the Same Ones?

    PubMed

    Rodríguez Mañas, Leocadio

    2015-01-01

    Older people are at risk of developing frailty with advancing age. The prevalence of frailty increases from 2.5-3% in adults aged 65 years to 30-35% in those older than 85 years. These results suggest that an association exists between longevity and frailty. However, at the same time, even at advanced age, the majority of older adults are free of frailty, suggesting that factors different from those contributing to or produced by the life length are involved in producing frailty. Genetic and epigenetic factors, nutrient-sensing systems, mainly the so-called insulin/insulin-like growth factor-1 signaling pathway, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, inflammation, and some hormonal systems are involved in longevity. However, factors involved in frailty are mainly inflammation and hormones, with an anecdotal role for genetic and other potential factors, but even these two common factors seem to regulate longevity and frailty in different ways. Moreover, their effect on frailty seems to change when they are acting in combination. PMID:26485702

  20. Is There a Role for Oligosaccharides in Seed Longevity? An Assessment of Intracellular Glass Stability1

    PubMed Central

    Buitink, Julia; Hemminga, Marcus A.; Hoekstra, Folkert A.

    2000-01-01

    We examined whether oligosaccharides extend seed longevity by increasing the intracellular glass stability. For that purpose, we used a spin probe technique to measure the molecular mobility and glass transition temperature of the cytoplasm of impatiens (Impatiens walleriana) and bell pepper (Capsicum annuum) seeds that were osmo-primed to change oligosaccharide content and longevity. Using saturation transfer electron paramagnetic resonance spectroscopy, we found that the rotational correlation time of the polar spin probe 3-carboxy-proxyl in the cytoplasm decreased, together with longevity, as a function of increasing seed water content, suggesting that longevity may indeed be regulated by cytoplasmic mobility. Osmo-priming of the seeds resulted in considerable decreases in longevity and oligosaccharide content, while the sucrose content increased. No difference in the glass transition temperature was found between control and primed impatiens seeds at the same temperature and water content. Similarly, there was no difference in the rotational motion of the spin probe in the cytoplasm between control and primed impatiens and bell pepper seeds. We therefore conclude that oligosaccharides in seeds do not affect the stability of the intracellular glassy state, and that the reduced longevity after priming is not the result of increased molecular mobility in the cytoplasm. PMID:10759518

  1. Fish oil supplements, longevity and aging.

    PubMed

    de Magalhães, João Pedro; Müller, Michael; Rainger, G Ed; Steegenga, Wilma

    2016-08-01

    Fish oil supplementation is of great medical and public interest with epidemiological evidence of health benefits in humans, in particular by conferring protection against heart diseases. Its anti-inflammatory properties have also been reported. Initial results from short-lived mouse strains showed that fish oil can increase lifespan, affecting pathways like inflammation and oxidation thought to be involved in the regulation of aging. Could fish oil and its omega-3 fatty acids act as geroprotectors? Probably not. A new study by Strong et al. challenges the role for fish oil supplementation in aging. Using a large cohort of genetically heterogeneous mice in three sites, part of the Interventions Testing Program of the NIA, Strong et al. show that fish oil supplementation at either low or high dosages has no effect on the lifespan of male or female mice. Although it is still possible that fish oil supplementation has health benefits for specific age-related diseases, it does not appear to slow aging or have longevity benefits. PMID:27564420

  2. Affiliative behavior attenuates stress responses of GI tract via up-regulating hypothalamic oxytocin expression.

    PubMed

    Babygirija, Reji; Cerjak, Diana; Yoshimoto, Sazu; Gribovskaja-Rupp, Irena; Bülbül, Mehmet; Ludwig, Kirk; Takahashi, Toku

    2012-07-01

    Hypothalamic oxytocin (OXT) has stress-attenuating effects. Social interaction in a positive environment continuously activates OXT release system. We have recently shown that pair housing restores delayed gastric emptying following chronic heterotypic stress, via up-regulation of OXT mRNA expression in rats. We tested the hypothesis that affiliative behavior attenuates stress responses via upregulating OXT expression. Adult male SD rats were divided into two groups: the rat with a stressed partner (RSP) and the rat with a non-stressed partner (RNSP). RSPs were pair housed with a partner that received different types of stress for 7 consecutive days (chronic heterotypic stress). RNSPs were pair housed with a partner who did not receive any stress. After each stress loading, the rats were returned to their home cages and the behaviors of RSPs and RNSPs toward their partners were videotaped. After the study completion, RSPs and RNSPs were loaded with acute restraint stress. Then, gastric emptying and colonic transit were measured. Corticotropin releasing factor (CRF) and OXT expression in the paraventricular nucleus (PVN) were evaluated by real time RT-PCR and immunohistochemistry. The time of affiliative behaviors toward their partners was increased in RSPs, compared to that of RNSPs. Delayed gastric emptying and accelerated colonic transit induced by acute restraint stress were significantly attenuated in RSPs, compared to RNSPs. CRF expression was reduced, while OXT expression was increased in RSPs in response to acute stress, compared to controls. It is suggested that affiliative behaviors may upregulate hypothalamic OXT expression, which in turn attenuates stress responses. PMID:22464293

  3. Macrophage migration inhibitory factor is an endogenous regulator of stress-induced extramedullary erythropoiesis.

    PubMed

    Vignjević Petrinović, Sanja; Budeč, Mirela; Marković, Dragana; Gotić, Mirjana; Mitrović Ajtić, Olivera; Mojsilović, Slavko; Stošić-Grujičić, Stanislava; Ivanov, Milan; Jovčić, Gordana; Čokić, Vladan

    2016-09-01

    Macrophage migration inhibitory factor is a well-known proinflammatory cytokine that is released during systemic stress response. Although MIF can affect erythrocyte production, the role of this cytokine in stress-induced erythropoiesis is completely unknown. To extend our previous findings showing that chronic psychological stress stimulates extramedullary erythropoiesis, here we examined whether MIF is involved in the control of stress-induced erythropoietic response. Adult male C57BL/6 wild-type (WT) and MIF-KO (knock-out) mice were subjected to 2-h daily restraint stress for either 7 or 14 consecutive days. The number of erythroid progenitors and CD71/Ter119 profile of erythroid precursors were analyzed in the bone marrow and spleen. Additionally, MIF protein expression was assessed in WT mice. Our results demonstrated that chronic restraint stress enhanced the number of both erythroid progenitors and precursors in the spleen. Stress-induced increase in the number of splenic late erythroid progenitors as well as in the percentage of CD71(+)Ter119(+)-double-positive precursors was significantly more pronounced in MIF-KO mice compared to WT animals. Furthermore, repeatedly stressed WT animals demonstrated an augmented MIF expression in the spleen. Unlike the spleen, the bone marrow of chronically stressed WT mice exhibited less prominent changes in erythropoietic stress response and no significant alteration in MIF expression. In addition, MIF deficiency did not influence the bone marrow erythropoiesis in stressed animals. These findings suggest that MIF regulates extramedullary erythropoiesis by inhibiting an overexpansion of splenic immature erythroid cells during chronic stress and indicate a novel role for this cytokine under chronic stress conditions. PMID:27129368

  4. Neurocircuitry Underlying Stress and Emotional Regulation in Animals Prenatally Exposed to Alcohol and Subjected to Chronic Mild Stress in Adulthood

    PubMed Central

    Raineki, Charlis; Hellemans, Kim G. C.; Bodnar, Tamara; Lavigne, Katie M.; Ellis, Linda; Woodward, Todd S.; Weinberg, Joanne

    2014-01-01

    Individuals exposed to alcohol during gestation show higher rates of psychopathologies. The hyperresponsivity to stress induced by prenatal alcohol exposure (PAE) may be related to this increased rate of psychopathologies, especially because this population is more likely to be exposed to stressful environments throughout life. However, alcohol-induced changes in the overlapping neurocircuitries that underlie stress and the expression of psychopathologies are not fully understood. Here, we performed a comprehensive analysis of the neural activity within central areas known to play key roles in both emotional and stress regulation. Adult male and female offspring from PAE, pair-fed, and ad libitum-fed control conditions were exposed to chronic mild stress (CMS). Following CMS, the neural activity (c-fos mRNA) of the amygdala, ventral hippocampal formation, medial prefrontal cortex (mPFC), and paraventricular nucleus of hypothalamus (PVN) was assessed in response to an acute stress (elevated plus maze). Our results demonstrate that, overall, PAE decreased neural activity within the amygdala and hippocampal formation in males and increased neural activity within the amygdala and mPFC in females. CMS reduced neural activity within the mPFC and PVN in PAE males, but reduced activity in all areas analyzed in control males. By contrast, CMS reduced neural activity in the mPFC in PAE females and had no effects in control females. Furthermore, the constrained principal component analysis revealed that these patterns of neural activity resulted in differential activation of the functional neural networks in males compared to females, indicating sexually dimorphic effects of PAE and CMS. Importantly, the altered networks of brain activation in PAE animals may underlie the hyperresponsivity to stress and increased psychopathologies observed among individuals prenatally exposed to alcohol. PMID:24592255

  5. Considerations on Temperature, Longevity and Aging

    PubMed Central

    Conti, Bruno

    2008-01-01

    A modest reduction in body temperature prolongs longevity and possibly retards aging in both poikilotherm and homeotherm animals. Some of the possible mechanisms mediating these effects are considered here with respect to major aging models and theories. PMID:18425417

  6. Oxidative Stress, Redox Regulation and Diseases of Cellular Differentiation

    PubMed Central

    Ye, Zhi-Wei; Zhang, Jie; Townsend, Danyelle M.; Tew, Kenneth D.

    2015-01-01

    Background Within cells, there is a narrow concentration threshold that governs whether reactive oxygen species (ROS) induce toxicity or act as second messengers. Scope of review We discuss current understanding of how ROS arise, facilitate cell signaling, cause toxicities and disease related to abnormal cell differentiation and those (primarily) sulfur based pathways that provide nucleophilicity to offset these effects. Primary conclusions Cellular redox homeostasis mediates a plethora of cellular pathways that determine life and death events. For example, ROS intersect with GSH based enzyme pathways to influence cell differentiation, a process integral to normal hematopoiesis, but also affecting a number of diverse cell differentiation related human diseases. Recent attempts to manage such pathologies have focused on intervening in some of these pathways, with the consequence that differentiation therapy targeting redox homeostasis has provided a platform for drug discovery and development. General Significance The balance between electrophilic oxidative stress and protective biomolecular nucleophiles predisposes the evolution of modern life forms. Imbalances of the two can produce aberrant redox homeostasis with resultant pathologies. Understanding the pathways involved provides opportunities to consider interventional strategies. PMID:25445706

  7. Deubiquitination and the regulation of stress granule assembly.

    PubMed

    Nostramo, R; Herman, P K

    2016-08-01

    Stress granules (SGs) are evolutionarily conserved ribonucleoprotein (RNP) structures that form in response to a variety of environmental and cellular cues. The presence of these RNP granules has been linked to a number of human diseases, including neurodegenerative disorders like amyotrophic lateral sclerosis (ALS) and spinocerebellar ataxia type 2 (Li et al., J Cell Biol 201:361-372, 2013; Nonhoff et al., Mol Biol Cell 18:1385-1396, 2007). Understanding how the assembly of these granules is controlled could, therefore, suggest possible routes of therapy for patients afflicted with these conditions. Interestingly, several reports have identified a potential role for protein deubiquitination in the assembly of these RNP granules. In particular, recent work has found that a specific deubiquitinase enzyme, Ubp3, is required for efficient SG formation in S. cerevisiae (Nostramo et al., Mol Cell Biol 36:173-183, 2016). This same enzyme has been linked to SGs in other organisms, including humans and the fission yeast, Schizosaccharomyces pombe (Takahashi et al., Mol Cell Biol 33:815-829, 2013; Wang et al., RNA 18:694-703, 2012). At first glance, these observations suggest that a striking degree of conservation exists for a ubiquitin-based mechanism controlling SG assembly. However, the devil is truly in the details here, as the precise nature of the involvement of this deubiquitinating enzyme seems to vary in each organism. Here, we briefly review these differences and attempt to provide an overarching model for the role of ubiquitin in SG formation. PMID:26852120

  8. Regulation of Non-coding RNAs in Heat Stress Responses of Plants

    PubMed Central

    Zhao, Jianguo; He, Qingsong; Chen, Gang; Wang, Li; Jin, Biao

    2016-01-01

    Heat stress is an important factor limiting plant growth, development, and productivity; thus, plants have evolved special adaptive mechanisms to cope with high-temperature stress. Non-coding RNAs (ncRNAs) are a class of regulatory RNAs that play an important role in many biological processes. Recently developed advanced technologies, such as genome-wide transcriptomic analysis, have revealed that abundant ncRNAs are expressed under heat stress. Although this area of research is still in its infancy, an increasing number of several classes of regulatory ncRNA (i.e., miRNA, siRNA, and lncRNA) related to heat stress responses have been reported. In this mini-review, we discuss our current understanding of the role of ncRNAs in heat stress responses in plants, especially miRNAs, siRNAs, and their targets. For example, the miR398-CSD/CCS-HSF, miR396-WRKY6, miR159-GAMYB, and TAS1-HTT-HSF pathways regulate plant heat tolerance. We highlight the hormone/development-related miRNAs involved in heat stress, and discuss the regulatory networks of miRNA-targets. We also note that DNA methylation and alternative splicing could affect miRNA expression under heat stress, and some lncRNAs could respond to heat stress. Finally, we briefly discuss future prospects concerning the ncRNA-related mechanisms of heat stress responses in plants. PMID:27588021

  9. Regulation of Non-coding RNAs in Heat Stress Responses of Plants.

    PubMed

    Zhao, Jianguo; He, Qingsong; Chen, Gang; Wang, Li; Jin, Biao

    2016-01-01

    Heat stress is an important factor limiting plant growth, development, and productivity; thus, plants have evolved special adaptive mechanisms to cope with high-temperature stress. Non-coding RNAs (ncRNAs) are a class of regulatory RNAs that play an important role in many biological processes. Recently developed advanced technologies, such as genome-wide transcriptomic analysis, have revealed that abundant ncRNAs are expressed under heat stress. Although this area of research is still in its infancy, an increasing number of several classes of regulatory ncRNA (i.e., miRNA, siRNA, and lncRNA) related to heat stress responses have been reported. In this mini-review, we discuss our current understanding of the role of ncRNAs in heat stress responses in plants, especially miRNAs, siRNAs, and their targets. For example, the miR398-CSD/CCS-HSF, miR396-WRKY6, miR159-GAMYB, and TAS1-HTT-HSF pathways regulate plant heat tolerance. We highlight the hormone/development-related miRNAs involved in heat stress, and discuss the regulatory networks of miRNA-targets. We also note that DNA methylation and alternative splicing could affect miRNA expression under heat stress, and some lncRNAs could respond to heat stress. Finally, we briefly discuss future prospects concerning the ncRNA-related mechanisms of heat stress responses in plants. PMID:27588021

  10. An index for longevity risk transfer

    NASA Astrophysics Data System (ADS)

    Denuit, Michel M.

    2009-08-01

    This paper discusses the choice of an appropriate longevity index to track the improvements in mortality in industrialized countries. Period life expectancies computed from national life tables turn out to be efficient in this context. A detailed analysis of the predictive distribution of this longevity index is performed in the Lee-Carter model where the period life expectancy is just a functional of the underlying time index.

  11. Posttraumatic stress symptoms and cortisol regulation in mothers of very preterm infants.

    PubMed

    Habersaat, Stephanie; Borghini, Ayala; Nessi, Jennifer; Pierrehumbert, Blaise; Forcada-Guex, Margarita; Ansermet, François; Müller-Nix, Carole

    2014-04-01

    Previous studies have found that mothers of very preterm infants often report symptoms of posttraumatic stress, which has been related to cortisol dysregulation. However, the exact nature of this association is not clear and can be different regarding the predominance of some specific symptoms of posttraumatic stress, as suggested by a recent model. The objective of the present study is to assess the association between diurnal salivary cortisol and posttraumatic stress symptoms in mothers of very preterm infants. Seventy-four mothers of very preterm infants were included in the study. Mothers' cortisol regulation and posttraumatic stress symptoms were evaluated 12 months after child theoretical term (40 weeks of gestation). Results showed an association between higher re-experiencing symptoms and flatter cortisol slopes. These results may help to understand differences found in studies assessing the relation between severity of posttraumatic stress and cortisol levels, by supporting the symptoms' theory. PMID:23824604

  12. Antagonistic interplay between hypocretin and leptin in the lateral hypothalamus regulates stress responses.

    PubMed

    Bonnavion, Patricia; Jackson, Alexander C; Carter, Matthew E; de Lecea, Luis

    2015-01-01

    The hypothalamic-pituitary-adrenal (HPA) axis functions to coordinate behavioural and physiological responses to stress in a manner that depends on the behavioural state of the organism. However, the mechanisms through which arousal and metabolic states influence the HPA axis are poorly understood. Here using optogenetic approaches in mice, we show that neurons that produce hypocretin (Hcrt)/orexin in the lateral hypothalamic area (LHA) regulate corticosterone release and a variety of behaviours and physiological hallmarks of the stress response. Interestingly, we found that Hcrt neuronal activity and Hcrt-mediated stress responses were inhibited by the satiety hormone leptin, which acts, in part, through a network of leptin-sensitive neurons in the LHA. These data demonstrate how peripheral metabolic signals interact with hypothalamic neurons to coordinate stress and arousal and suggest one mechanism through which hyperarousal or altered metabolic states may be linked with abnormal stress responses. PMID:25695914

  13. Regulation of water, salinity, and cold stress responses by salicylic acid

    PubMed Central

    Miura, Kenji; Tada, Yasuomi

    2014-01-01

    Salicylic acid (SA) is a naturally occurring phenolic compound. SA plays an important role in the regulation of plant growth, development, ripening, and defense responses. The role of SA in the plant–pathogen relationship has been extensively investigated. In addition to defense responses, SA plays an important role in the response to abiotic stresses, including drought, low temperature, and salinity stresses. It has been suggested that SA has great agronomic potential to improve the stress tolerance of agriculturally important crops. However, the utility of SA is dependent on the concentration of the applied SA, the mode of application, and the state of the plants (e.g., developmental stage and acclimation). Generally, low concentrations of applied SA alleviate the sensitivity to abiotic stresses, and high concentrations of applied induce high levels of oxidative stress, leading to a decreased tolerance to abiotic stresses. In this article, the effects of SA on the water stress responses and regulation of stomatal closure are reviewed. PMID:24478784

  14. Salt stress encourages proline accumulation by regulating proline biosynthesis and degradation in Jerusalem artichoke plantlets.

    PubMed

    Huang, Zengrong; Zhao, Long; Chen, Dandan; Liang, Mingxiang; Liu, Zhaopu; Shao, Hongbo; Long, Xiaohua

    2013-01-01

    Proline accumulation is an important mechanism for osmotic regulation under salt stress. In this study, we evaluated proline accumulation profiles in roots, stems and leaves of Jerusalem artichoke (Helianthus tuberosus L.) plantlets under NaCl stress. We also examined HtP5CS, HtOAT and HtPDH enzyme activities and gene expression patterns of putative HtP5CS1, HtP5CS2, HtOAT, HtPDH1, and HtPDH2 genes. The objective of our study was to characterize the proline regulation mechanisms of Jerusalem artichoke, a moderately salt tolerant species, under NaCl stress. Jerusalem artichoke plantlets were observed to accumulate proline in roots, stems and leaves during salt stress. HtP5CS enzyme activities were increased under NaCl stress, while HtOAT and HtPDH activities generally repressed. Transcript levels of HtP5CS2 increased while transcript levels of HtOAT, HtPDH1 and HtPDH2 generally decreased in response to NaCl stress. Our results supports that for Jerusalem artichoke, proline synthesis under salt stress is mainly through the Glu pathway, and HtP5CS2 is predominant in this process while HtOAT plays a less important role. Both HtPDH genes may function in proline degradation. PMID:23637970

  15. Salt Stress Encourages Proline Accumulation by Regulating Proline Biosynthesis and Degradation in Jerusalem Artichoke Plantlets

    PubMed Central

    Huang, Zengrong; Zhao, Long; Chen, Dandan; Liang, Mingxiang; Liu, Zhaopu; Shao, Hongbo; Long, Xiaohua

    2013-01-01

    Proline accumulation is an important mechanism for osmotic regulation under salt stress. In this study, we evaluated proline accumulation profiles in roots, stems and leaves of Jerusalem artichoke (Helianthus tuberosus L.) plantlets under NaCl stress. We also examined HtP5CS, HtOAT and HtPDH enzyme activities and gene expression patterns of putative HtP5CS1, HtP5CS2, HtOAT, HtPDH1, and HtPDH2 genes. The objective of our study was to characterize the proline regulation mechanisms of Jerusalem artichoke, a moderately salt tolerant species, under NaCl stress. Jerusalem artichoke plantlets were observed to accumulate proline in roots, stems and leaves during salt stress. HtP5CS enzyme activities were increased under NaCl stress, while HtOAT and HtPDH activities generally repressed. Transcript levels of HtP5CS2 increased while transcript levels of HtOAT, HtPDH1 and HtPDH2 generally decreased in response to NaCl stress. Our results supports that for Jerusalem artichoke, proline synthesis under salt stress is mainly through the Glu pathway, and HtP5CS2 is predominant in this process while HtOAT plays a less important role. Both HtPDH genes may function in proline degradation. PMID:23637970

  16. Manganese regulation of virulence factors and oxidative stress resistance in Neisseria gonorrhoeae

    PubMed Central

    Wu, Hsing-Ju; Seib, Kate L.; Srikhanta, Yogitha N.; Edwards, Jennifer; Kidd, Stephen P.; Maguire, Tina L .; Hamilton, Amanda; Pan, Kuan-Tin; Hsiao, He-Hsuan; Yao, Chen-Wen; Grimmond, Sean M.; Apicella, Michael A.; McEwan, Alastair G.; Wang, Andrew H-J.; Jennings, Michael P.

    2014-01-01

    Neisseria gonorrhoeae has evolved a complex and novel network of oxidative stress responses, including defense mechanisms that are dependent on manganese (Mn). We performed systematic analyses at the transcriptomic and proteomic (1D SDS-PAGE and Isotope-Coded Affinity Tag [ICAT]) levels to investigate the global expression changes that take place in a high Mn environment, which results in a Mn-dependent oxidative stress resistance phenotype. These studies revealed that 97 proteins are regulated at the post-transcriptional level under conditions of increased Mn concentration, including proteins involved in virulence (eg. Pilin, a key adhesin), oxidative stress defence (eg. superoxide dismutase), cellular metabolism, protein synthesis, RNA processing and cell division. Mn regulation of inorganic pyrophosphatase (Ppa) indicated the potential involvement of phosphate metabolism in the Mn-dependent oxidative stress defense. A detailed analysis of the role of Ppa and polyphosphate kinase (Ppk) in the gonococcal oxidative stress response revealed that ppk and ppa mutant strains showed increased resistance to oxidative stress. Investigation of these mutants grown with high Mn suggests that phosphate and pyrophosphate are involved in Mn-dependent oxidative stress resistance. PMID:20004262

  17. Acute psychosocial stress and emotion regulation skills modulate empathic reactions to pain in others.

    PubMed

    Buruck, Gabriele; Wendsche, Johannes; Melzer, Marlen; Strobel, Alexander; Dörfel, Denise

    2014-01-01

    Psychosocial stress affects resources for adequate coping with environmental demands. A crucial question in this context is the extent to which acute psychosocial stressors impact empathy and emotion regulation. In the present study, 120 participants were randomly assigned to a control group vs. a group confronted with the Trier Social Stress Test (TSST), an established paradigm for the induction of acute psychosocial stress. Empathy for pain as a specific subgroup of empathy was assessed via pain intensity ratings during a pain-picture task. Self-reported emotion regulation skills were measured as predictors using an established questionnaire. Stressed individuals scored significantly lower on the appraisal of pain pictures. A regression model was chosen to find variables that further predict the pain ratings. These findings implicate that acute psychosocial stress might impair empathic processes to observed pain in another person and the ability to accept one's emotion additionally predicts the empathic reaction. Furthermore, the ability to tolerate negative emotions modulated the relation between stress and pain judgments, and thus influenced core cognitive-affective functions relevant for coping with environmental challenges. In conclusion, our study emphasizes the necessity of reducing negative emotions in terms of empathic distress when confronted with pain of another person under psychosocial stress, in order to be able to retain pro-social behavior. PMID:24910626

  18. EphB2 in the Medial Prefrontal Cortex Regulates Vulnerability to Stress.

    PubMed

    Zhang, Ruo-Xi; Han, Ying; Chen, Chen; Xu, Ling-Zhi; Li, Jia-Li; Chen, Na; Sun, Cheng-Yu; Chen, Wen-Hao; Zhu, Wei-Li; Shi, Jie; Lu, Lin

    2016-09-01

    The ephrin B2 (EphB2) receptor is a tyrosine kinase receptor that is associated with synaptic development and maturation. It has recently been implicated in cognitive deficits and anxiety. However, still unknown is the involvement of EphB2 in the vulnerability to stress. In the present study, we observed decreases in EphB2 levels and their downstream molecules in the medial prefrontal cortex (mPFC) but not in the orbitofrontal cortex (OFC) in mice that were susceptible to chronic social defeat stress. The activation of EphB2 receptors with EphrinB1-Fc in the mPFC produced stress-resistant and antidepressant-like behavioral effects in susceptible mice that lasted for at least 10 days. EphB2 receptor knockdown by short-hairpin RNA in the mPFC increased the susceptibility to stress and induced depressive-like behaviors in a subthreshold chronic social defeat stress paradigm. These behavioral effects were associated with changes in the phosphorylation of cofilin and membrane α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) trafficking and the expression of some synaptic proteins in the mPFC. We also found that EphB2 regulated stress-induced spine remodeling in the mPFC. Altogether, these results indicate that EphB2 is a critical regulator of stress vulnerability and might be a potential target for the treatment of depression. PMID:27103064

  19. Stress Regulates Aquaporin-8 Permeability to Impact Cell Growth and Survival

    PubMed Central

    Medraño-Fernandez, Iria; Bestetti, Stefano; Bertolotti, Milena; Bienert, Gerd P.; Bottino, Cinzia; Laforenza, Umberto; Rubartelli, Anna

    2016-01-01

    Abstract Aquaporin-8 (AQP8) allows the bidirectional transport of water and hydrogen peroxide across biological membranes. Depending on its concentration, H2O2 exerts opposite roles, amplifying growth factor signaling in physiological conditions, but causing severe cell damage when in excess. Thus, H2O2 permeability is likely to be tightly controlled in living cells. Aims: In this study, we investigated whether and how the transport of H2O2 through plasma membrane AQP8 is regulated, particularly during cell stress. Results: We show that diverse cellular stress conditions, including heat, hypoxia, and ER stress, reversibly inhibit the permeability of AQP8 to H2O2 and water. Preventing the accumulation of intracellular reactive oxygen species (ROS) during stress counteracts AQP8 blockade. Once inhibition is established, AQP8-dependent transport can be rescued by reducing agents. Neither H2O2 nor water transport is impaired in stressed cells expressing a mutant AQP8, in which cysteine 53 had been replaced by serine. Cells expressing this mutant are more resistant to stress-, drug-, and radiation-induced growth arrest and death. Innovation and Conclusion: The control of AQP8-mediated H2O2 transport provides a novel mechanism to regulate cell signaling and survival during stress. Antioxid. Redox Signal. 24, 1031–1044. PMID:26972385

  20. Coping with Stresses: Roles of Calcium- and Calcium/Calmodulin-Regulated Gene Expression[W][OA

    PubMed Central

    Reddy, Anireddy S.N.; Ali, Gul S.; Celesnik, Helena; Day, Irene S.

    2011-01-01

    Abiotic and biotic stresses are major limiting factors of crop yields and cause billions of dollars of losses annually around the world. It is hoped that understanding at the molecular level how plants respond to adverse conditions and adapt to a changing environment will help in developing plants that can better cope with stresses. Acquisition of stress tolerance requires orchestration of a multitude of biochemical and physiological changes, and most of these depend on changes in gene expression. Research during the last two decades has established that different stresses cause signal-specific changes in cellular Ca2+ level, which functions as a messenger in modulating diverse physiological processes that are important for stress adaptation. In recent years, many Ca2+ and Ca2+/calmodulin (CaM) binding transcription factors (TFs) have been identified in plants. Functional analyses of some of these TFs indicate that they play key roles in stress signaling pathways. Here, we review recent progress in this area with emphasis on the roles of Ca2+- and Ca2+/CaM-regulated transcription in stress responses. We will discuss emerging paradigms in the field, highlight the areas that need further investigation, and present some promising novel high-throughput tools to address Ca2+-regulated transcriptional networks. PMID:21642548

  1. Acute psychosocial stress and emotion regulation skills modulate empathic reactions to pain in others

    PubMed Central

    Buruck, Gabriele; Wendsche, Johannes; Melzer, Marlen; Strobel, Alexander; Dörfel, Denise

    2014-01-01

    Psychosocial stress affects resources for adequate coping with environmental demands. A crucial question in this context is the extent to which acute psychosocial stressors impact empathy and emotion regulation. In the present study, 120 participants were randomly assigned to a control group vs. a group confronted with the Trier Social Stress Test (TSST), an established paradigm for the induction of acute psychosocial stress. Empathy for pain as a specific subgroup of empathy was assessed via pain intensity ratings during a pain-picture task. Self-reported emotion regulation skills were measured as predictors using an established questionnaire. Stressed individuals scored significantly lower on the appraisal of pain pictures. A regression model was chosen to find variables that further predict the pain ratings. These findings implicate that acute psychosocial stress might impair empathic processes to observed pain in another person and the ability to accept one's emotion additionally predicts the empathic reaction. Furthermore, the ability to tolerate negative emotions modulated the relation between stress and pain judgments, and thus influenced core cognitive-affective functions relevant for coping with environmental challenges. In conclusion, our study emphasizes the necessity of reducing negative emotions in terms of empathic distress when confronted with pain of another person under psychosocial stress, in order to be able to retain pro-social behavior. PMID:24910626

  2. Overexpression of Protochlorophyllide Oxidoreductase C Regulates Oxidative Stress in Arabidopsis

    PubMed Central

    Pattanayak, Gopal K.; Tripathy, Baishnab C.

    2011-01-01

    Light absorbed by colored intermediates of chlorophyll biosynthesis is not utilized in photosynthesis; instead, it is transferred to molecular oxygen, generating singlet oxygen (1O2). As there is no enzymatic detoxification mechanism available in plants to destroy 1O2, its generation should be minimized. We manipulated the concentration of a major chlorophyll biosynthetic intermediate i.e., protochlorophyllide in Arabidopsis by overexpressing the light-inducible protochlorophyllide oxidoreductase C (PORC) that effectively phototransforms endogenous protochlorophyllide to chlorophyllide leading to minimal accumulation of the photosensitizer protochlorophyllide in light-grown plants. In PORC overexpressing (PORCx) plants exposed to high-light, the 1O2 generation and consequent malonedialdehyde production was minimal and the maximum quantum efficiency of photosystem II remained unaffected demonstrating that their photosynthetic apparatus and cellular organization were intact. Further, PORCx plants treated with 5-aminolevulinicacid when exposed to light, photo-converted over-accumulated protochlorophyllide to chlorophyllide, reduced the generation of 1O2 and malonedialdehyde production and reduced plasma membrane damage. So PORCx plants survived and bolted whereas, the 5-aminolevulinicacid-treated wild-type plants perished. Thus, overexpression of PORC could be biotechnologically exploited in crop plants for tolerance to 1O2-induced oxidative stress, paving the use of 5-aminolevulinicacid as a selective commercial light-activated biodegradable herbicide. Reduced protochlorophyllide content in PORCx plants released the protochlorophyllide-mediated feed-back inhibition of 5-aminolevulinicacid biosynthesis that resulted in higher 5-aminolevulinicacid production. Increase of 5-aminolevulinicacid synthesis upregulated the gene and protein expression of several downstream chlorophyll biosynthetic enzymes elucidating a regulatory net work of expression of genes involved in 5

  3. Associations between STR autosomal markers and longevity.

    PubMed

    Bediaga, N G; Aznar, J M; Elcoroaristizabal, X; Albóniga, O; Gómez-Busto, F; Artaza Artabe, I; Rocandio, Ana; de Pancorbo, M M

    2015-10-01

    Life span is a complex and multifactorial trait, which is shaped by genetic, epigenetic, environmental, and stochastic factors. The possibility that highly hypervariable short tandem repeats (STRs) associated with longevity has been largely explored by comparing the genotypic pools of long lived and younger individuals, but results so far have been contradictory. In view of these contradictory findings, the present study aims to investigate whether HUMTHO1 and HUMCSF1PO STRs, previously associated with longevity, exert a role as a modulator of life expectancy, as well as to assess the extent to which other autosomal STR markers are associated with human longevity in population from northern Spain. To that end, 21 autosomal microsatellite markers have been studied in 304 nonagenarian individuals (more than 90 years old) and 516 younger controls of European descent. Our results do not confirm the association found in previous studies between longevity and THO1 and CSF1PO loci. However, significant association between longevity and autosomal STR markers D12S391, D22S1045, and DS441 was observed. Even more, when we compared allelic frequency distribution of the 21 STR markers between cases and controls, we found that 6 out of the 21 STRs studied showed different allelic frequencies, thus suggesting that the genomic portrait of the human longevity is far complex and probably shaped by a high number of genomic loci. PMID:26335621

  4. IRAF: Lessons for Project Longevity

    NASA Astrophysics Data System (ADS)

    Fitzpatrick, M.

    2012-09-01

    Although sometimes derided as a product of the 80's (or more generously, as a legacy system), the fact that IRAF remains a productive work environment for many astronomers today is a testament to one of its core design principles, portability. This idea has meaning beyond a survey of platforms in use at the peak of a project's active development; for true longevity, a project must be able to weather completely unimagined OS, hardware, data, staffing and political environments. A lack of attention to the broader issues of portability, or the true lifespan of a software system (e.g. archival science may extend for years beyond a given mission, upgraded or similar instruments may be developed that require the same reduction/analysis techniques, etc) might require costly new software development instead of simple code re-use. Additionally, one under-appreciated benefit to having a long history in the community is the trust that users have established in the science results produced by a particular system. However a software system evolves architecturally, preserving this trust (and by implication, the applications themselves) is the key to continued success. In this paper, we will discuss how the system architecture has allowed IRAF to navigate the many changes in computing since it was first released. It is hoped that the lessons learned can be adopted by software systems being built today so that they too can survive long enough to one day earn the distinction of being called a legacy system.

  5. Endoplasmic reticulum stress up-regulates Nedd4-2 to induce autophagy.

    PubMed

    Wang, Hao; Sun, Ruo-Qiong; Camera, Daria; Zeng, Xiao-Yi; Jo, Eunjung; Chan, Stanley M H; Herbert, Terence P; Molero, Juan C; Ye, Ji-Ming

    2016-07-01

    The accumulation of unfolded proteins within the endoplasmic reticulum (ER) causes ER stress and activation of unfolded protein response (UPR). This response can trigger ER-associated degradation and autophagy, which clear unfolded proteins and restore protein homeostasis. Recently, it has become clear that ubiquitination plays an important role in the regulation of autophagy. In the present study, we investigated how the E3 ubiquitin ligase neural precursor cell-expressed, developmentally down-regulated protein 4-2 (Nedd4-2) interacts with ER stress and autophagy. In mice, we found that an increase in the expression of Nedd4-2, which was concomitant with the activation of the UPR and autophagy, was caused by a prolonged high-fructose and high-fat diet that induces ER stress in the liver. Pharmacologic induction of ER stress also led to an increase in Nedd4-2 expression in cultured cells, which was coincident with UPR and autophagy activation. The inhibition of inositol-requiring enzyme 1 significantly suppressed Nedd4-2 expression. Moreover, increased Nedd4-2 expression in vivo was closely associated with the activation of inositol-requiring enzyme 1 and increased expression of the spliced form of X-box binding protein 1. Furthermore, knockdown of Nedd4-2 in cultured cells suppressed both basal autophagy and ER stress-induced autophagy, whereas overexpression of Nedd4-2-induced autophagy. Taken together, our findings provide evidence that Nedd4-2 is up-regulated in response to ER stress by the spliced form of X-box binding protein 1 and that this is important in the induction of an appropriate autophagic response.-Wang, H. Sun, R.-Q., Camera, D., Zeng, X.-Y., Jo, E., Chan, S. M. H., Herbert, T. P., Molero, J. C., Ye, J.-M. Endoplasmic reticulum stress up-regulates Nedd4-2 to induce autophagy. PMID:27022162

  6. Activation and regulation of the Spc1 stress-activated protein kinase in Schizosaccharomyces pombe.

    PubMed

    Degols, G; Shiozaki, K; Russell, P

    1996-06-01

    Spc1, an osmotic-stress-stimulated mitogen-activated protein kinase (MAPK) homolog in the fission yeast Schizosaccharomyces pombe, is required for the induction of mitosis and survival in high-osmolarity conditions. Spc1, also known as Sty1, is activated by Wis1 MAPK kinase and inhibited by Pyp1 tyrosine phosphatase. Spc1 is most closely related to Saccharomyces cerevisiae Hog1 and mammalian p38 kinases. Whereas Hog1 is specifically responsive to osmotic stress, we report here that Spc1 is activated by multiple forms of stress, including high temperature and oxidative stress. In this regard Spc1 is more similar to mammalian p38. Activation of Spc1 is crucial for survival of various forms of stress. Spc1 regulates expression of genes encoding stress-related proteins such as glycerol-3-phosphate dehydrogenase (gpd1+) and trehalose-6-phosphate synthase (tps1+). Spc1 also promotes expression of pyp2+, which encodes a tyrosine phosphatase postulated as a negative regulator of Spc1. This proposal is supported by the finding that Spc1 associates with Pyp2 in vivo and that the amount of Spc1 tyrosine phosphorylation is lower in a Pyp2-overproducing strain than in the wild type. Moreover, the level of stress-stimulated gpd1+ expression is higher in delta pyp2 mutants than in the wild type. These findings demonstrate that Spc1 promotes expression of genes involved in stress survival and that of regulation may be commonly employed to modulate MAPK signal transduction pathways in eukaryotic species. PMID:8649397

  7. Stress-associated erythropoiesis initiation is regulated by type 1 conventional dendritic cells.

    PubMed

    Kim, Taeg S; Hanak, Mark; Trampont, Paul C; Braciale, Thomas J

    2015-10-01

    Erythropoiesis is an important response to certain types of stress, including hypoxia, hemorrhage, bone marrow suppression, and anemia, that result in inadequate tissue oxygenation. This stress-induced erythropoiesis is distinct from basal red blood cell generation; however, neither the cellular nor the molecular factors that regulate this process are fully understood. Here, we report that type 1 conventional dendritic cells (cDC1s), which are defined by expression of CD8α in the mouse and XCR1 and CLEC9 in humans, are critical for induction of erythropoiesis in response to stress. Specifically, using murine models, we determined that engagement of a stress sensor, CD24, on cDC1s upregulates expression of the Kit ligand stem cell factor on these cells. The increased expression of stem cell factor resulted in Kit-mediated proliferative expansion of early erythroid progenitors and, ultimately, transient reticulocytosis in the circulation. Moreover, this stress response was triggered in part by alarmin recognition and was blunted in CD24 sensor- and CD8α+ DC-deficient animals. The contribution of the cDC1 subset to the initiation of stress erythropoiesis was distinct from the well-recognized role of macrophages in supporting late erythroid maturation. Together, these findings offer insight into the mechanism of stress erythropoiesis and into disorders of erythrocyte generation associated with stress. PMID:26389678

  8. GABAA receptor-acting neurosteroids: A role in the development and regulation of the stress response

    PubMed Central

    Gunn, Benjamin G.; Cunningham, Linda; Mitchell, Scott G.; Swinny, Jerome D.; Lambert, Jeremy J.; Belelli, Delia

    2015-01-01

    Regulation of hypothalamic–pituitary–adrenocortical (HPA) axis activity by stress is a fundamental survival mechanism and HPA-dysfunction is implicated in psychiatric disorders. Adverse early life experiences, e.g. poor maternal care, negatively influence brain development and programs an abnormal stress response by encoding long-lasting molecular changes, which may extend to the next generation. How HPA-dysfunction leads to the development of affective disorders is complex, but may involve GABAA receptors (GABAARs), as they curtail stress-induced HPA axis activation. Of particular interest are endogenous neurosteroids that potently modulate the function of GABAARs and exhibit stress-protective properties. Importantly, neurosteroid levels rise rapidly during acute stress, are perturbed in chronic stress and are implicated in the behavioural changes associated with early-life adversity. We will appraise how GABAAR-active neurosteroids may impact on HPA axis development and the orchestration of the stress-evoked response. The significance of these actions will be discussed in the context of stress-associated mood disorders. PMID:24929099

  9. Stress-associated erythropoiesis initiation is regulated by type 1 conventional dendritic cells

    PubMed Central

    Kim, Taeg S.; Hanak, Mark; Trampont, Paul C.; Braciale, Thomas J.

    2015-01-01

    Erythropoiesis is an important response to certain types of stress, including hypoxia, hemorrhage, bone marrow suppression, and anemia, that result in inadequate tissue oxygenation. This stress-induced erythropoiesis is distinct from basal red blood cell generation; however, neither the cellular nor the molecular factors that regulate this process are fully understood. Here, we report that type 1 conventional dendritic cells (cDC1s), which are defined by expression of CD8α in the mouse and XCR1 and CLEC9 in humans, are critical for induction of erythropoiesis in response to stress. Specifically, using murine models, we determined that engagement of a stress sensor, CD24, on cDC1s upregulates expression of the Kit ligand stem cell factor on these cells. The increased expression of stem cell factor resulted in Kit-mediated proliferative expansion of early erythroid progenitors and, ultimately, transient reticulocytosis in the circulation. Moreover, this stress response was triggered in part by alarmin recognition and was blunted in CD24 sensor– and CD8α+ DC-deficient animals. The contribution of the cDC1 subset to the initiation of stress erythropoiesis was distinct from the well-recognized role of macrophages in supporting late erythroid maturation. Together, these findings offer insight into the mechanism of stress erythropoiesis and into disorders of erythrocyte generation associated with stress. PMID:26389678

  10. The effects of prolonged exposure and sertraline on emotion regulation in individuals with posttraumatic stress disorder.

    PubMed

    Jerud, Alissa B; Pruitt, Larry D; Zoellner, Lori A; Feeny, Norah C

    2016-02-01

    The effects of current posttraumatic stress disorder (PTSD) interventions on emotion regulation are relatively unknown. Many conceptualize PTSD as a disorder of emotion dysregulation, and clinicians often fear that emotion regulation impairments will not change with stand-alone PTSD treatments, particularly for individuals with pre-existing emotion regulation difficulties. The present study examined changes in emotion regulation (expressive suppression, cognitive reappraisal, negative mood regulation) with prolonged exposure (PE) therapy or sertraline, specifically examining whether those with higher pre-existing emotion regulation difficulties improved over treatment on these indices. Individuals with chronic PTSD (N = 200) received 10 weeks of PE or sertraline and were followed through 6-month follow-up. Emotion regulation was assessed at pre- and post-treatment and at 3- and 6-month follow-up. Individuals with poorer initial emotion regulation showed greater improvement on all indices of emotion regulation, regardless of which treatment they received. Changes occurred during active treatment and were maintained over follow-up. These findings have both theoretical and clinical implications, arguing that emotion regulation is not impaired across all individuals with PTSD and that PE and sertraline effectively address emotion regulation difficulties. PMID:26723004

  11. Stress and serial adult metamorphosis: multiple roles for the stress axis in socially regulated sex change

    PubMed Central

    Solomon-Lane, Tessa K.; Crespi, Erica J.; Grober, Matthew S.

    2013-01-01

    Socially regulated sex change in teleost fishes is a striking example of social status information regulating biological function in the service of reproductive success. The establishment of social dominance in sex changing species is translated into a cascade of changes in behavior, physiology, neuroendocrine function, and morphology that transforms a female into a male, or vice versa. The hypothalamic-pituitary-interrenal axis (HPI, homologous to HP-adrenal axis in mammals and birds) has been hypothesized to play a mechanistic role linking status to sex change. The HPA/I axis responds to environmental stressors by integrating relevant external and internal cues and coordinating biological responses including changes in behavior, energetics, physiology, and morphology (i.e., metamorphosis). Through actions of both corticotropin-releasing factor and glucocorticoids, the HPA/I axis has been implicated in processes central to sex change, including the regulation of agonistic behavior, social status, energetic investment, and life history transitions. In this paper, we review the hypothesized roles of the HPA/I axis in the regulation of sex change and how those hypotheses have been tested to date. We include original data on sex change in the bluebanded goby (Lythyrpnus dalli), a highly social fish capable of bidirectional sex change. We then propose a model for HPA/I involvement in sex change and discuss how these ideas might be tested in the future. Understanding the regulation of sex change has the potential to elucidate evolutionarily conserved mechanisms responsible for translating pertinent information about the environment into coordinated biological changes along multiple body axes. PMID:24265604

  12. Specific microRNAs regulate heat stress responses in Caenorhabditis elegans.

    PubMed

    Nehammer, Camilla; Podolska, Agnieszka; Mackowiak, Sebastian D; Kagias, Konstantinos; Pocock, Roger

    2015-01-01

    The ability of animals to sense and respond to elevated temperature is essential for survival. Transcriptional control of the heat stress response has been much studied, whereas its posttranscriptional regulation by microRNAs (miRNAs) is not well understood. Here we analyzed the miRNA response to heat stress in Caenorhabditis elegans and show that a discrete subset of miRNAs is thermoregulated. Using in-depth phenotypic analyses of miRNA deletion mutant strains we reveal multiple developmental and post-developmental survival and behavioral functions for specific miRNAs during heat stress. We have identified additional functions for already known players (mir-71 and mir-239) as well as identifying mir-80 and the mir-229 mir-64-66 cluster as important regulators of the heat stress response in C. elegans. These findings uncover an additional layer of complexity to the regulation of stress signaling that enables animals to robustly respond to the changing environment. PMID:25746291

  13. Specific microRNAs Regulate Heat Stress Responses in Caenorhabditis elegans

    PubMed Central

    Nehammer, Camilla; Podolska, Agnieszka; Mackowiak, Sebastian D.; Kagias, Konstantinos; Pocock, Roger

    2015-01-01

    The ability of animals to sense and respond to elevated temperature is essential for survival. Transcriptional control of the heat stress response has been much studied, whereas its posttranscriptional regulation by microRNAs (miRNAs) is not well understood. Here we analyzed the miRNA response to heat stress in Caenorhabditis elegans and show that a discrete subset of miRNAs is thermoregulated. Using in-depth phenotypic analyses of miRNA deletion mutant strains we reveal multiple developmental and post-developmental survival and behavioral functions for specific miRNAs during heat stress. We have identified additional functions for already known players (mir-71 and mir-239) as well as identifying mir-80 and the mir-229 mir-64-66 cluster as important regulators of the heat stress response in C. elegans. These findings uncover an additional layer of complexity to the regulation of stress signaling that enables animals to robustly respond to the changing environment. PMID:25746291

  14. Regulation of oxidative stress resistance in Campylobacter jejuni, a microaerophilic foodborne pathogen

    PubMed Central

    Kim, Jong-Chul; Oh, Euna; Kim, Jinyong; Jeon, Byeonghwa

    2015-01-01

    Campylobacter jejuni is one of the leading bacterial causes of human gastroenteritis. Due to the increasing rates of human campylobacteriosis, C. jejuni is considered as a serious public health concern worldwide. C. jejuni is a microaerophilic, fastidious bacterium. C. jejuni must overcome a wide range of stress conditions during foodborne transmission to humans, such as food preservation and processing conditions, and even in infection of the gastrointestinal tracts of humans. Particularly, this microaerophilic foodborne pathogen must survive in the atmospheric conditions prior to the initiation of infection. C. jejuni possesses unique regulatory mechanisms for oxidative stress resistance. Lacking OxyR and SoxRS that are highly conserved in other Gram-negative foodborne pathogens, C. jejuni modulates the expression of genes involved in oxidative stress resistance mainly via the peroxide resistance regulator and Campylobacter oxidative stress regulator. Based on recent findings of ours and others, in this review, we described how C. jejuni regulates the expression of oxidative stress defense. PMID:26284041

  15. The Arabidopsis RNA-binding protein AtRGGA regulates tolerance to salt and drought stress.

    PubMed

    Ambrosone, Alfredo; Batelli, Giorgia; Nurcato, Roberta; Aurilia, Vincenzo; Punzo, Paola; Bangarusamy, Dhinoth Kumar; Ruberti, Ida; Sassi, Massimiliano; Leone, Antonietta; Costa, Antonello; Grillo, Stefania

    2015-05-01

    Salt and drought stress severely reduce plant growth and crop productivity worldwide. The identification of genes underlying stress response and tolerance is the subject of intense research in plant biology. Through microarray analyses, we previously identified in potato (Solanum tuberosum) StRGGA, coding for an Arginine Glycine Glycine (RGG) box-containing RNA-binding protein, whose expression was specifically induced in potato cell cultures gradually exposed to osmotic stress. Here, we show that the Arabidopsis (Arabidopsis thaliana) ortholog, AtRGGA, is a functional RNA-binding protein required for a proper response to osmotic stress. AtRGGA gene expression was up-regulated in seedlings after long-term exposure to abscisic acid (ABA) and polyethylene glycol, while treatments with NaCl resulted in AtRGGA down-regulation. AtRGGA promoter analysis showed activity in several tissues, including stomata, the organs controlling transpiration. Fusion of AtRGGA with yellow fluorescent protein indicated that AtRGGA is localized in the cytoplasm and the cytoplasmic perinuclear region. In addition, the rgga knockout mutant was hypersensitive to ABA in root growth and survival tests and to salt stress during germination and at the vegetative stage. AtRGGA-overexpressing plants showed higher tolerance to ABA and salt stress on plates and in soil, accumulating lower levels of proline when exposed to drought stress. Finally, a global analysis of gene expression revealed extensive alterations in the transcriptome under salt stress, including several genes such as ASCORBATE PEROXIDASE2, GLUTATHIONE S-TRANSFERASE TAU9, and several SMALL AUXIN UPREGULATED RNA-like genes showing opposite expression behavior in transgenic and knockout plants. Taken together, our results reveal an important role of AtRGGA in the mechanisms of plant response and adaptation to stress. PMID:25783413

  16. The Intersection of Aging, Longevity Pathways, and Learning and Memory in C. elegans

    PubMed Central

    Stein, Geneva M.; Murphy, Coleen T.

    2012-01-01

    Our understanding of the molecular and genetic regulation of aging and longevity has been greatly augmented through studies using the small model system, C. elegans. It is important to test whether mutations that result in a longer life span also extend the health span of the organism, rather than simply prolonging an aged state. C. elegans can learn and remember both associated and non-associated stimuli, and many of these learning and memory paradigms are subject to regulation by longevity pathways. One of the more distressing results of aging is cognitive decline, and while no gross physical defects in C. elegans sensory neurons have been identified, the organism does lose the ability to perform both simple and complex learned behaviors with age. Here we review what is known about the effects of longevity pathways and the decline of these complex learned behaviors with age, and we highlight outstanding questions in the field. PMID:23226155

  17. S-Nitrosylation Positively Regulates Ascorbate Peroxidase Activity during Plant Stress Responses1

    PubMed Central

    Yang, Huanjie; Mu, Jinye; Chen, Lichao; Feng, Jian; Hu, Jiliang; Li, Lei; Zhou, Jian-Min; Zuo, Jianru

    2015-01-01

    Nitric oxide (NO) and reactive oxygen species (ROS) are two classes of key signaling molecules involved in various developmental processes and stress responses in plants. The burst of NO and ROS triggered by various stimuli activates downstream signaling pathways to cope with abiotic and biotic stresses. Emerging evidence suggests that the interplay of NO and ROS plays a critical role in regulating stress responses. However, the underpinning molecular mechanism remains poorly understood. Here, we show that NO positively regulates the activity of the Arabidopsis (Arabidopsis thaliana) cytosolic ascorbate peroxidase1 (APX1). We found that S-nitrosylation of APX1 at cysteine (Cys)-32 enhances its enzymatic activity of scavenging hydrogen peroxide, leading to the increased resistance to oxidative stress, whereas a substitution mutation at Cys-32 causes the reduction of ascorbate peroxidase activity and abolishes its responsiveness to the NO-enhanced enzymatic activity. Moreover, S-nitrosylation of APX1 at Cys-32 also plays an important role in regulating immune responses. These findings illustrate a unique mechanism by which NO regulates hydrogen peroxide homeostasis in plants, thereby establishing a molecular link between NO and ROS signaling pathways. PMID:25667317

  18. FurA contributes to the oxidative stress response regulation of Mycobacterium avium ssp. paratuberculosis

    PubMed Central

    Eckelt, Elke; Meißner, Thorsten; Meens, Jochen; Laarmann, Kristin; Nerlich, Andreas; Jarek, Michael; Weiss, Siegfried; Gerlach, Gerald-F.; Goethe, Ralph

    2015-01-01

    The ferric uptake regulator A (FurA) is known to be involved in iron homeostasis and stress response in many bacteria. In mycobacteria the precise role of FurA is still unclear. In the presented study, we addressed the functional role of FurA in the ruminant pathogen Mycobacterium avium ssp. paratuberculosis (MAP) by construction of a furA deletion strain (MAPΔfurA). RNA deep sequencing revealed that the FurA regulon consists of repressed and activated genes associated to stress response or intracellular survival. Not a single gene related to metal homeostasis was affected by furA deletion. A decisive role of FurA during intracellular survival in macrophages was shown by significantly enhanced survival of MAPΔfurA compared to the wildtype, indicating that a principal task of mycobacterial FurA is oxidative stress response regulation in macrophages. This resistance was not associated with altered survival of mice after long term infection with MAP. Our results demonstrate for the first time, that mycobacterial FurA is not involved in the regulation of iron homeostasis. However, they provide strong evidence that FurA contributes to intracellular survival as an oxidative stress sensing regulator. PMID:25705205

  19. Severity of Children's ADHD Symptoms and Parenting Stress: A Multiple Mediation Model of Self-Regulation

    ERIC Educational Resources Information Center

    Graziano, Paulo A.; McNamara, Joseph P.; Geffken, Gary R.; Reid, Adam

    2011-01-01

    The goal of the current study was to determine the extent to which the perceived self-regulation deficits across behavioral, cognitive, and emotional domains seen in children with ADHD explain the association between the severity of ADHD symptoms and parenting stress. Participants for this study included 80 children (mean age = 10 years, 9 months)…

  20. GABAergic regulation of the HPA and HPG axes and the impact of stress on reproductive function.

    PubMed

    Camille Melón, Laverne; Maguire, Jamie

    2016-06-01

    The hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes are regulated by GABAergic signaling at the level of corticotropin-releasing hormone (CRH) and gonadotropin-releasing hormone (GnRH) neurons, respectively. Under basal conditions, activity of CRH and GnRH neurons are controlled in part by both phasic and tonic GABAergic inhibition, mediated by synaptic and extrasynaptic GABAA receptors (GABAARs), respectively. For CRH neurons, this tonic GABAergic inhibition is mediated by extrasynaptic, δ subunit-containing GABAARs. Similarly, a THIP-sensitive tonic GABAergic current has been shown to regulate GnRH neurons, suggesting a role for δ subunit-containing GABAARs; however, this remains to be explicitly demonstrated. GABAARs incorporating the δ subunit confer neurosteroid sensitivity, suggesting a potential role for neurosteroid modulation in the regulation of the HPA and HPG axes. Thus, stress-derived neurosteroids may contribute to the impact of stress on reproductive function. Interestingly, excitatory actions of GABA have been demonstrated in both CRH neurons at the apex of control of the HPA axis and in GnRH neurons which mediate the HPG axis, adding to the complexity for the role of GABAergic signaling in the regulation of these systems. Here we review the effects that stress has on GnRH neurons and HPG axis function alongside evidence supporting GABAARs as a major interface between the stress and reproductive axes. PMID:26690789

  1. Therapeutic Alliance, Negative Mood Regulation, and Treatment Outcome in Child Abuse-Related Posttraumatic Stress Disorder

    ERIC Educational Resources Information Center

    Cloitre, Marylene; Chase Stovall McClough,K.; Miranda, Regina; Chemtob, Claude M.

    2004-01-01

    This study examined the related contributions of the therapeutic alliance and negative mood regulation to the outcome of a 2-phase treatment for childhood abuse-related posttraumatic stress disorder (PTSD). Phase 1 focused on stabilization and preparatory skills building, whereas Phase 2 was comprised primarily of imaginal exposure to traumatic…

  2. Up-regulated expression of Ran reveals its potential role to deltamethrin stress in Kc cells.

    PubMed

    Liu, Wei; Xu, Qin; Chi, Qingping; Hu, Junli; Li, Fengliang; Cheng, Luogen

    2016-05-25

    The GTP-binding nuclear protein Ran has mostly been reported to be an essential player in nuclear transport, chromosome alignment, microtubule dynamics, centrosome duplication, kinetochore attachment of microtubules, nuclear-envelope dynamics, and phagocytosis. However, until now, there has been no report showing the involvement of Ran in DM stress. In this paper, two-dimensional electrophoresis analysis showed that the expression level of Ran in Kc cells in response to DM was higher than that in the control group. In addition, quantitative analysis using real-time PCR revealed that the expression of Ran was obviously up-regulated at various concentrations of DM. Western blot analysis showed that Ran was up-regulated 2.27-fold over the control at 48h. Because we still could not pinpoint whether Ran was actually involved in DM stress reaction, to further verify the role of Ran in stress reaction, RNA interference and cell transfection were utilized. Overexpression of Ran in cells conferred a degree of protection against DM after 72h. Furthermore, interference with Ran significantly decrease cell viability. All of the above findings strongly imply that Ran may participate in the development of stress reaction to DM. Therefore, investigating the possible role of Ran in DM stress will broaden our limited knowledge regarding DM stress inducible genes. PMID:26924245

  3. Arabidopsis microRNA expression regulation in a wide range of abiotic stress responses

    PubMed Central

    Barciszewska-Pacak, Maria; Milanowska, Kaja; Knop, Katarzyna; Bielewicz, Dawid; Nuc, Przemyslaw; Plewka, Patrycja; Pacak, Andrzej M.; Vazquez, Franck; Karlowski, Wojciech; Jarmolowski, Artur; Szweykowska-Kulinska, Zofia

    2015-01-01

    Arabidopsis microRNA expression regulation was studied in a wide array of abiotic stresses such as drought, heat, salinity, copper excess/deficiency, cadmium excess, and sulfur deficiency. A home-built RT-qPCR mirEX platform for the amplification of 289 Arabidopsis microRNA transcripts was used to study their response to abiotic stresses. Small RNA sequencing, Northern hybridization, and TaqMan® microRNA assays were performed to study the abundance of mature microRNAs. A broad response on the level of primary miRNAs (pri-miRNAs) was observed. However, stress response at the level of mature microRNAs was rather confined. The data presented show that in most instances, the level of a particular mature miRNA could not be predicted based on the level of its pri-miRNA. This points to an essential role of posttranscriptional regulation of microRNA expression. New Arabidopsis microRNAs responsive to abiotic stresses were discovered. Four microRNAs: miR319a/b, miR319b.2, and miR400 have been found to be responsive to several abiotic stresses and thus can be regarded as general stress-responsive microRNA species. PMID:26089831

  4. Oxytocin buffers cortisol responses to stress in individuals with impaired emotion regulation abilities.

    PubMed

    Quirin, Markus; Kuhl, Julius; Düsing, Rainer

    2011-07-01

    Oxytocin facilitates stress regulation but little is known about individual differences in this effect. The present study investigates whether the effect of intranasal oxytocin on stress-contingent cortisol release differs between individuals with high vs. low emotional regulation abilities (ERA). In a double-blind study thirty-six healthy male students with either high or low ERA were randomly assigned to receive intranasally 24 IU oxytocin or placebo. Cortisol was measured at several times before and after a social stressor (public speaking). Individuals with impaired ERA showed a reduced cortisol response to stress after oxytocin but an increased cortisol response after placebo application. The results suggest that healthy individuals with low ERA benefit from intranasal oxytocin application. Neurobiological mechanisms potentially underlying the link between oxytocin, cortsiol and ERA are discussed against the background of a neuroendocrinological perspective on personality. PMID:21208748

  5. Coordinated regulation of photosynthesis in rice increases yield and tolerance to environmental stress

    PubMed Central

    Ambavaram, Madana M. R.; Basu, Supratim; Krishnan, Arjun; Ramegowda, Venkategowda; Batlang, Utlwang; Rahman, Lutfor; Baisakh, Niranjan; Pereira, Andy

    2014-01-01

    Plants capture solar energy and atmospheric carbon dioxide (CO2) through photosynthesis, which is the primary component of crop yield, and needs to be increased considerably to meet the growing global demand for food. Environmental stresses, which are increasing with climate change, adversely affect photosynthetic carbon metabolism (PCM) and limit yield of cereals such as rice (Oryza sativa) that feeds half the world. To study the regulation of photosynthesis, we developed a rice gene regulatory network and identified a transcription factor HYR (HIGHER YIELD RICE) associated with PCM, which on expression in rice enhances photosynthesis under multiple environmental conditions, determining a morpho-physiological programme leading to higher grain yield under normal, drought and high-temperature stress conditions. We show HYR is a master regulator, directly activating photosynthesis genes, cascades of transcription factors and other downstream genes involved in PCM and yield stability under drought and high-temperature environmental stress conditions. PMID:25358745

  6. ATF4 is involved in the regulation of simulated microgravity induced integrated stress response

    NASA Astrophysics Data System (ADS)

    Li, Yingxian; Li, Qi; Wang, Xiaogang; Sun, Qiao; Wan, Yumin; Li, Yinghui; Bai, Yanqiang

    Objective: Many important metabolic and signaling pathways have been identified as being affected by microgravity, thereby altering cellular functions such as proliferation, differentiation, maturation and cell survival. It has been demonstrated that microgravity could induce all kinds of stress response such as endoplasmic reticulum stress and oxidative stress et al. ATF4 belongs to the ATF/CREB family of basic region leucine zipper transcription factors. ATF4 is induced by stress signals including anoxia/hypoxia, ER stress, amino acid deprivation and oxidative stress. ATF4 regulates the expression of genes involved in oxidative stress, amino acid synthesis, differentiation, metastasis and angiogenesis. The aim of this study was to examine the changes of ATF4 under microgravity, and to investigate the role of ATF4 in microgravity induced stress. MethodsMEF cells were cultured in clinostat to simulate microgravity. Reverse transcription polymerase chain reaction (RT-PCR) and western blotting were used to examine mRNA and protein levels of ATF4 expression under simulated microgravity in MEF cells. ROS levels were measured with the use of the fluorescent signal H2DCF-DA. GFP-XBP1 stably transfected cell lines was used to detect the extent of ER stress under microgravity by the intensity of GFP. Dual luciferase reporter assay was used to detect the activity of ATF4. Co-immunoprecipitation was performed to analyze protein interaction. Results: ATF4 protein levels in MEF cells increased under simulated microgravity. However, ATF4 mRNA levels were consistent. XBP1 splicing can be induced due to ER stress caused by simulated microgravity. At the same time, ROS levels were also increased. Increased ATF4 could promote the expression of CHOP, which is responsible for cell apoptosis. ATF4 also play an important role in cellular anti-oxidant stress. In ATF4 -/-MEF cells, the ROS levels after H2O2 treatment were obviously higher than that of wild type cells. HDAC4 was

  7. The Pepper CaOSR1 Protein Regulates the Osmotic Stress Response via Abscisic Acid Signaling

    PubMed Central

    Park, Chanmi; Lim, Chae Woo; Lee, Sung Chul

    2016-01-01

    Plants are sessile organisms, and their growth and development is detrimentally affected by environmental stresses such as drought and high salinity. Defense mechanisms are tightly regulated and complex processes, which respond to changing environmental conditions; however, the precise mechanisms that function under adverse conditions remain unclear. Here, we report the identification and functional characterization of the CaOSR1 gene, which functions in the adaptive response to abiotic stress. We found that CaOSR1 gene expression in pepper leaves was up-regulated after exposure to abscisic acid (ABA), drought, and high salinity. In addition, we demonstrated that the fusion protein of CaOSR1 with green fluorescent protein (GFP) is localized in the nucleus. We used CaOSR1-silenced pepper plants and CaOSR1-OX-overexpressing (OX) transgenic Arabidopsis plants to show that the CaOSR1 protein regulates the osmotic stress response. CaOSR1-silenced pepper plants showed increased drought susceptibility, and this was accompanied by a high transpiration rate. CaOSR1-OX plants displayed phenotypes that were hypersensitive to ABA and hyposensitive to osmotic stress, during the seed germination and seedling growth stages; furthermore, these plants exhibited enhanced drought tolerance at the adult stage, and this was characterized by higher leaf temperatures and smaller stomatal apertures because of ABA hypersensitivity. Taken together, our data indicate that CaOSR1 positively regulates osmotic stress tolerance via ABA-mediated cell signaling. These findings suggest an involvement of a novel protein in ABA and osmotic stress signalings in plants. PMID:27446121

  8. The Pepper CaOSR1 Protein Regulates the Osmotic Stress Response via Abscisic Acid Signaling.

    PubMed

    Park, Chanmi; Lim, Chae Woo; Lee, Sung Chul

    2016-01-01

    Plants are sessile organisms, and their growth and development is detrimentally affected by environmental stresses such as drought and high salinity. Defense mechanisms are tightly regulated and complex processes, which respond to changing environmental conditions; however, the precise mechanisms that function under adverse conditions remain unclear. Here, we report the identification and functional characterization of the CaOSR1 gene, which functions in the adaptive response to abiotic stress. We found that CaOSR1 gene expression in pepper leaves was up-regulated after exposure to abscisic acid (ABA), drought, and high salinity. In addition, we demonstrated that the fusion protein of CaOSR1 with green fluorescent protein (GFP) is localized in the nucleus. We used CaOSR1-silenced pepper plants and CaOSR1-OX-overexpressing (OX) transgenic Arabidopsis plants to show that the CaOSR1 protein regulates the osmotic stress response. CaOSR1-silenced pepper plants showed increased drought susceptibility, and this was accompanied by a high transpiration rate. CaOSR1-OX plants displayed phenotypes that were hypersensitive to ABA and hyposensitive to osmotic stress, during the seed germination and seedling growth stages; furthermore, these plants exhibited enhanced drought tolerance at the adult stage, and this was characterized by higher leaf temperatures and smaller stomatal apertures because of ABA hypersensitivity. Taken together, our data indicate that CaOSR1 positively regulates osmotic stress tolerance via ABA-mediated cell signaling. These findings suggest an involvement of a novel protein in ABA and osmotic stress signalings in plants. PMID:27446121

  9. A cocaine-regulated and amphetamine-regulated transcript inhibits oxidative stress in neurons deprived of oxygen and glucose.

    PubMed

    Sha, Dujuan; Wang, Zhongyuan; Qian, Lai; Han, Yong; Zhang, Jun; Gu, Shuangshuang; Wang, Luna; Li, Jie; Chen, Cong; Xu, Yun

    2013-09-11

    Stroke, of which about 87% is ischemic stroke, constitutes one of the main causes of morbidity, disability, and mortality worldwide. Ischemic brain injury has complex pathological mechanisms. Considerable evidence has been collected over the last few years suggesting that oxidative stress associated with excessive production of reactive oxygen species is a fundamental mechanism of brain damage in stroke and reperfusion after stroke. Oxidative stress is an important trigger of neuronal apoptosis in ischemic stroke. In this current study, it was found that cocaine-regulated and amphetamine-regulated transcript 55-102 (CART55-102) inhibited oxygen-induced and glucose deprivation (OGD)-induced neurotoxicity in a dose-dependent manner. The peak dose of CART55-102 was 0.4 nmol/l. In addition, the level of intracellular reactive oxygen species was decreased in OGD-treated neurons in the presence of 0.4 nmol/l CART55-102. Mitochondrial membrane potential (ΔΨm) and mtDNA mRNA expressions were increased in OGD-treated neurons in the presence of 0.4 nmol/l CART55-102. The current study suggests that CART55-102, by inhibiting oxidative stress, may be developed into therapeutic agents for ischemic stroke. PMID:23884173

  10. Longevity of orders is related to the longevity of their constituent genera rather than genus richness.

    PubMed

    Bornholdt, Stefan; Sneppen, Kim; Westphal, Hildegard

    2009-05-01

    Longevity of a taxonomic group is an important issue in understanding the dynamics of evolution. In this respect a key observation is that genera, families or orders can each be assigned a characteristic average lifetime (Van Valen in Evol Theory 1:1-30, 1973). Using the fossil marine animal genera database (Sepkoski in Bull Am Paleontol 363, pp 563, 2002) we here examine the relationship between longevity of a higher taxonomic group (orders) and the longevity of its lower taxonomic groups (genera). We find insignificant correlation between the size of an order and its longevity, whereas we observe large correlation between the lifetime of an order and the lifetime of its constituent genera. These observations suggest that longevity of taxonomic groups is heritable intrinsically or on the grounds of environmental preferences. PMID:19101746

  11. Coordinate Regulation of Metabolite Glycosylation and Stress Hormone Biosynthesis by TT8 in Arabidopsis.

    PubMed

    Rai, Amit; Umashankar, Shivshankar; Rai, Megha; Kiat, Lim Boon; Bing, Johanan Aow Shao; Swarup, Sanjay

    2016-08-01

    Secondary metabolites play a key role in coordinating ecology and defense strategies of plants. Diversity of these metabolites arises by conjugation of core structures with diverse chemical moieties, such as sugars in glycosylation. Active pools of phytohormones, including those involved in plant stress response, are also regulated by glycosylation. While much is known about the enzymes involved in glycosylation, we know little about their regulation or coordination with other processes. We characterized the flavonoid pathway transcription factor TRANSPARENT TESTA8 (TT8) in Arabidopsis (Arabidopsis thaliana) using an integrative omics strategy. This approach provides a systems-level understanding of the cellular machinery that is used to generate metabolite diversity by glycosylation. Metabolomics analysis of TT8 loss-of-function and inducible overexpression lines showed that TT8 coordinates glycosylation of not only flavonoids, but also nucleotides, thus implicating TT8 in regulating pools of activated nucleotide sugars. Transcriptome and promoter network analyses revealed that the TT8 regulome included sugar transporters, proteins involved in sugar binding and sequestration, and a number of carbohydrate-active enzymes. Importantly, TT8 affects stress response, along with brassinosteroid and jasmonic acid biosynthesis, by directly binding to the promoters of key genes of these processes. This combined effect on metabolite glycosylation and stress hormones by TT8 inducible overexpression led to significant increase in tolerance toward multiple abiotic and biotic stresses. Conversely, loss of TT8 leads to increased sensitivity to these stresses. Thus, the transcription factor TT8 is an integrator of secondary metabolism and stress response. These findings provide novel approaches to improve broad-spectrum stress tolerance. PMID:27432888

  12. Coordinate Regulation of Metabolite Glycosylation and Stress Hormone Biosynthesis by TT8 in Arabidopsis1[OPEN

    PubMed Central

    Kiat, Lim Boon

    2016-01-01

    Secondary metabolites play a key role in coordinating ecology and defense strategies of plants. Diversity of these metabolites arises by conjugation of core structures with diverse chemical moieties, such as sugars in glycosylation. Active pools of phytohormones, including those involved in plant stress response, are also regulated by glycosylation. While much is known about the enzymes involved in glycosylation, we know little about their regulation or coordination with other processes. We characterized the flavonoid pathway transcription factor TRANSPARENT TESTA8 (TT8) in Arabidopsis (Arabidopsis thaliana) using an integrative omics strategy. This approach provides a systems-level understanding of the cellular machinery that is used to generate metabolite diversity by glycosylation. Metabolomics analysis of TT8 loss-of-function and inducible overexpression lines showed that TT8 coordinates glycosylation of not only flavonoids, but also nucleotides, thus implicating TT8 in regulating pools of activated nucleotide sugars. Transcriptome and promoter network analyses revealed that the TT8 regulome included sugar transporters, proteins involved in sugar binding and sequestration, and a number of carbohydrate-active enzymes. Importantly, TT8 affects stress response, along with brassinosteroid and jasmonic acid biosynthesis, by directly binding to the promoters of key genes of these processes. This combined effect on metabolite glycosylation and stress hormones by TT8 inducible overexpression led to significant increase in tolerance toward multiple abiotic and biotic stresses. Conversely, loss of TT8 leads to increased sensitivity to these stresses. Thus, the transcription factor TT8 is an integrator of secondary metabolism and stress response. These findings provide novel approaches to improve broad-spectrum stress tolerance. PMID:27432888

  13. CtsR Is the Master Regulator of Stress Response Gene Expression in Oenococcus oeni

    PubMed Central

    Grandvalet, Cosette; Coucheney, Françoise; Beltramo, Charlotte; Guzzo, Jean

    2005-01-01

    Although many stress response genes have been characterized in Oenococcus oeni, little is known about the regulation of stress response in this malolactic bacterium. The expression of eubacterial stress genes is controlled both positively and negatively at the transcriptional level. Overall, negative regulation of heat shock genes appears to be more widespread among gram-positive bacteria. We recently identified an ortholog of the ctsR gene in O. oeni. In Bacillus subtilis, CtsR negatively regulates expression of the clp genes, which belong to the class III family of heat shock genes. The ctsR gene of O. oeni is cotranscribed with the downstream clpC gene. Sequence analysis of the O. oeni IOB 8413 (ATCC BAA-1163) genome revealed the presence of potential CtsR operator sites upstream from most of the major molecular chaperone genes, including the clp genes and the groES and dnaK operons. Using B. subtilis as a heterologous host, CtsR-dependent regulation of O. oeni molecular chaperone genes was demonstrated with transcriptional fusions. No alternative sigma factors appear to be encoded by the O. oeni IOB 8413 (ATCC BAA-1163) genome. Moreover, apart from CtsR, no known genes encoding regulators of stress response, such as HrcA, could be identified in this genome. Unlike the multiple regulatory mechanisms of stress response described in many closely related gram-positive bacteria, this is the first example where dnaK and groESL are controlled by CtsR but not by HrcA. PMID:16077106

  14. Signalling mucin Msb2 Regulates adaptation to thermal stress in Candida albicans

    PubMed Central

    Saraswat, Darpan; Kumar, Rohitashw; Pande, Tanaya; Edgerton, Mira; Cullen, Paul J.

    2016-01-01

    Summary Temperature is a potent inducer of fungal dimorphism. Multiple signalling pathways control the response to growth at high temperature, but the sensors that regulate these pathways are poorly defined. We show here that the signalling mucin Msb2 is a global regulator of temperature stress in the fungal pathogen Candida albicans. Msb2 was required for survival and hyphae formation at 42°C. The cytoplasmic signalling domain of Msb2 regulated temperature-dependent activation of the CEK mitogen activated proteins kinase (MAPK) pathway. The extracellular glycosylated domain of Msb2 (100–900 amino acid residues) had a new and unexpected role in regulating the protein kinase C (PKC) pathway. Msb2 also regulated temperature-dependent induction of genes encoding regulators and targets of the unfolded protein response (UPR), which is a protein quality control (QC) pathway in the endoplasmic reticulum that controls protein folding/degradation in response to high temperature and other stresses. The heat shock protein and cell wall component Ssa1 was also required for hyphae formation and survival at 42° C and regulated the CEK and PKC pathways. PMID:26749104

  15. Epigenetic regulation of repetitive elements is attenuated by prolonged heat stress in Arabidopsis.

    PubMed

    Pecinka, Ales; Dinh, Huy Q; Baubec, Tuncay; Rosa, Marisa; Lettner, Nicole; Mittelsten Scheid, Ortrun

    2010-09-01

    Epigenetic factors determine responses to internal and external stimuli in eukaryotic organisms. Whether and how environmental conditions feed back to the epigenetic landscape is more a matter of suggestion than of substantiation. Plants are suitable organisms with which to address this question due to their sessile lifestyle and diversification of epigenetic regulators. We show that several repetitive elements of Arabidopsis thaliana that are under epigenetic regulation by transcriptional gene silencing at ambient temperatures and upon short term heat exposure become activated by prolonged heat stress. Activation can occur without loss of DNA methylation and with only minor changes to histone modifications but is accompanied by loss of nucleosomes and by heterochromatin decondensation. Whereas decondensation persists, nucleosome loading and transcriptional silencing are restored upon recovery from heat stress but are delayed in mutants with impaired chromatin assembly functions. The results provide evidence that environmental conditions can override epigenetic regulation, at least transiently, which might open a window for more permanent epigenetic changes. PMID:20876829

  16. Exploring mechanisms of sex differences in longevity: lifetime ovary exposure and exceptional longevity in dogs.

    PubMed

    Waters, David J; Kengeri, Seema S; Clever, Beth; Booth, Julie A; Maras, Aimee H; Schlittler, Deborah L; Hayek, Michael G

    2009-12-01

    To move closer to understanding the mechanistic underpinnings of sex differences in human longevity, we studied pet dogs to determine whether lifetime duration of ovary exposure was associated with exceptional longevity. This hypothesis was tested by collecting and analyzing lifetime medical histories, age at death, and cause of death for a cohort of canine 'centenarians'--exceptionally long-lived Rottweiler dogs that lived more than 30% longer than average life expectancy for the breed. Sex and lifetime ovary exposure in the oldest-old Rottweilers (age at death, > or = 13 years) were compared to a cohort of Rottweilers that had usual longevity (age at death, 8.0-10.8 years). Like women, female dogs were more likely than males to achieve exceptional longevity (OR, 95% CI = 2.0, 1.2-3.3; P = 0.006). However, removal of ovaries during the first 4 years of life erased the female survival advantage. In females, a strong positive association between ovaries and longevity persisted in multivariate analysis that considered other factors, such as height, body weight, and mother with exceptional longevity. A beneficial effect of ovaries on longevity in females could not be attributed to resistance against a particular disease or major cause of death. Our results document in dogs a female sex advantage for achieving exceptional longevity and show that lifetime ovary exposure, a factor not previously evaluated in women, is associated with exceptional longevity. This work introduces a conceptual framework for designing additional studies in pet dogs to define the ovary-sensitive biological processes that promote healthy human longevity. PMID:19732047

  17. Persistent transcription-blocking DNA lesions trigger somatic growth attenuation associated with longevity

    PubMed Central

    Garinis, George A.; Uittenboogaard, Lieneke M.; Stachelscheid, Heike; Fousteri, Maria; van Ijcken, Wilfred; Breit, Timo M.; van Steeg, Harry; Mullenders, Leon H.F.; van der Horst, Gijsbertus T.J.; Brüning, Jens C.; Niessen, Carien M.; Hoeijmakers, Jan H.J.; Schumacher, Björn

    2009-01-01

    Accumulation of stochastic DNA damage throughout organisms’ lifespan is thought to contribute to aging. Conversely, aging appears phenotypically reproducible and regulated through genetic pathways such as the insulin-like growth factor-1 (IGF-1) and growth hormone (GH) receptors, which are central mediators of the somatic growth axis. Here, we report that persistent DNA damage in primary cells elicits similar changes in global gene expression as those occurring in various organs of naturally aged animals. Importantly, we show that, as in aging animals, IGF-1 receptor and GH receptor expression is attenuated resulting in cellular IGF-1 resistance. This cell-autonomous attenuation is specifically induced by persistent lesions leading to RNA polymerase II stalling, in proliferating, quiescent and terminally differentiated cells, is exacerbated and prolonged in cells from progeroid mice and confers resistance to oxidative stress. Our findings suggest that DNA damage accumulation in transcribed genes in most if not all tissues, contributes to the aging-associated shift from growth to somatic maintenance that triggers stress resistance and is thought to promote longevity. PMID:19363488

  18. Integrin-linked kinase modulates longevity and thermotolerance in C. elegans through neuronal control of HSF-1

    PubMed Central

    Kumsta, Caroline; Ching, Tsui-Ting; Nishimura, Mayuko; Davis, Andrew E; Gelino, Sara; Catan, Hannah H; Yu, Xiaokun; Chu, Chu-Chiao; Ong, Binnan; Panowski, Siler H; Baird, Nathan; Bodmer, Rolf; Hsu, Ao-Lin; Hansen, Malene

    2014-01-01

    Integrin-signaling complexes play important roles in cytoskeletal organization and cell adhesion in many species. Components of the integrin-signaling complex have been linked to aging in both Caenorhabditis elegans and Drosophila melanogaster, but the mechanism underlying this function is unknown. Here, we investigated the role of integrin-linked kinase (ILK), a key component of the integrin-signaling complex, in lifespan determination. We report that genetic reduction of ILK in both C. elegans and Drosophila increased resistance to heat stress, and led to lifespan extension in C. elegans without majorly affecting cytoskeletal integrity. In C. elegans, longevity and thermotolerance induced by ILK depletion was mediated by heat-shock factor-1 (HSF-1), a major transcriptional regulator of the heat-shock response (HSR). Reduction in ILK levels increased hsf-1 transcription and activation, and led to enhanced expression of a subset of genes with roles in the HSR. Moreover, induction of HSR-related genes, longevity and thermotolerance caused by ILK reduction required the thermosensory neurons AFD and interneurons AIY, which are known to play a critical role in the canonical HSR. Notably, ILK was expressed in neighboring neurons, but not in AFD or AIY, implying that ILK reduction initiates cell nonautonomous signaling through thermosensory neurons to elicit a noncanonical HSR. Our results thus identify HSF-1 as a novel effector of the organismal response to reduced ILK levels and show that ILK inhibition regulates HSF-1 in a cell nonautonomous fashion to enhance stress resistance and lifespan in C. elegans. PMID:24314125

  19. A putative TetR regulator is involved in nitric oxide stress resistance in Porphyromonas gingivalis.

    PubMed

    Boutrin, M-C; Yu, Y; Wang, C; Aruni, W; Dou, Y; Shi, L; Fletcher, H M

    2016-08-01

    To survive in the periodontal pocket, Porphyromonas gingivalis, the main causative agent of periodontal disease, must overcome oxidative and nitric oxide (NO) stress. Previously, we reported that, in the presence of NO comparable to stress conditions, the transcriptome of P. gingivalis was differentially expressed, and genes belonging to the PG1178-81 cluster were significantly upregulated. To further evaluate their role(s) in NO stress resistance, these genes were inactivated by allelic exchange mutagenesis. Isogenic mutants P. gingivalis FLL460 (ΔPG1181::ermF) and FLL461 (ΔPG1178-81::ermF) were black-pigmented, with gingipain and hemolytic activities comparable to that of the wild-type strain. Whereas the recovery of these isogenic mutants from NO stress was comparable to the wild-type, there was increased sensitivity to hydrogen peroxide-induced stress. RNA-Seq analysis under conditions of NO stress showed that approximately 5 and 8% of the genome was modulated in P. gingivalis FLL460 and FLL461, respectively. The PG1178-81 gene cluster was shown to be part of the same transcriptional unit and is inducible in response to NO stress. In the presence of NO, PG1181, a putative transcriptional regulator, was shown to bind to its own promoter region and that of several other NO responsive genes including PG0214 an extracytoplasmic function σ factor, PG0893 and PG1236. Taken together, the data suggest that PG1181 is a NO responsive transcriptional regulator that may play an important role in the NO stress resistance regulatory network in P. gingivalis. PMID:26332057

  20. Abiotic stress responses in plants: roles of calmodulin-regulated proteins

    PubMed Central

    Virdi, Amardeep S.; Singh, Supreet; Singh, Prabhjeet

    2015-01-01

    Intracellular changes in calcium ions (Ca2+) in response to different biotic and abiotic stimuli are detected by various sensor proteins in the plant cell. Calmodulin (CaM) is one of the most extensively studied Ca2+-sensing proteins and has been shown to be involved in transduction of Ca2+ signals. After interacting with Ca2+, CaM undergoes conformational change and influences the activities of a diverse range of CaM-binding proteins. A number of CaM-binding proteins have also been implicated in stress responses in plants, highlighting the central role played by CaM in adaptation to adverse environmental conditions. Stress adaptation in plants is a highly complex and multigenic response. Identification and characterization of CaM-modulated proteins in relation to different abiotic stresses could, therefore, prove to be essential for a deeper understanding of the molecular mechanisms involved in abiotic stress tolerance in plants. Various studies have revealed involvement of CaM in regulation of metal ions uptake, generation of reactive oxygen species and modulation of transcription factors such as CAMTA3, GTL1, and WRKY39. Activities of several kinases and phosphatases have also been shown to be modulated by CaM, thus providing further versatility to stress-associated signal transduction pathways. The results obtained from contemporary studies are consistent with the proposed role of CaM as an integrator of different stress signaling pathways, which allows plants to maintain homeostasis between different cellular processes. In this review, we have attempted to present the current state of understanding of the role of CaM in modulating different stress-regulated proteins and its implications in augmenting abiotic stress tolerance in plants. PMID:26528296

  1. Genome size and longevity in fish.

    PubMed

    Griffith, O L; Moodie, G E E; Civetta, A

    2003-03-01

    The wide variety of genome sizes (measured as C-value) observed across taxa is not related to organismal complexity or number of coding genes. Partial answers to this C-value enigma have been found by establishing associations between C-value and particular phenotypic characteristics. One such controversial association has been recently suggested between genome size and longevity in birds. In order to determine whether genome size is a general predictor of longevity, we have extended the analysis to the Actinoptergyian fish, a widely divergent group in terms of both longevity and genome size. We collected data on genome size, longevity and body mass for species covering fourteen orders of bony fish. Analysis of covariance using order as a cofactor shows a significant effect of genome size on longevity (corrected for body mass), with lifespan increasing as a function of genome size. Analysis of phylogenetically independent contrasts for orders with a large number of species with a well resolved phylogenetic relationship (Acipenseriformes, Cypriniformes, and Salmoniformes) found the same trend of longer lifespan with increases in genome size but the relationship was not significant. Our results consistently show an increase in lifespan for fish with larger genomes. PMID:12581799

  2. Galactinol as marker for seed longevity.

    PubMed

    de Souza Vidigal, Deborah; Willems, Leo; van Arkel, Jeroen; Dekkers, Bas J W; Hilhorst, Henk W M; Bentsink, Leónie

    2016-05-01

    Reduced seed longevity or storability is a major problem in seed storage and contributes to increased costs in crop production. Here we investigated whether seed galactinol contents could be predictive for seed storability behavior in Arabidopsis, cabbage and tomato. The analyses revealed a positive correlation between galactinol content and seed longevity in the three species tested, which indicates that this correlation is conserved in the Brassicaceae and beyond. Quantitative trait loci (QTL) mapping in tomato revealed a co-locating QTL for galactinol content and seed longevity on chromosome 2. A candidate for this QTL is the GALACTINOL SYNTHASE gene (Solyc02g084980.2.1) that is located in the QTL interval. GALACTINOL SYNTHASE is a key enzyme of the raffinose family oligosaccharide (RFO) pathway. To investigate the role of enzymes in the RFO pathway in more detail, we applied a reverse genetics approach using T-DNA knock-out lines in genes encoding enzymes of this pathway (GALACTINOL SYNTHASE 1, GALACTINOL SYNTHASE 2, RAFFINOSE SYNTHASE, STACHYOSE SYNTHASE and ALPHA-GALACTOSIDASE) and overexpressors of the cucumber GALACTINOL SYNTHASE 2 gene in Arabidopsis. The galactinol synthase 2 mutant and the galactinol synthase 1 galactinol synthase 2 double mutant contained the lowest seed galactinol content which coincided with lower seed longevity. These results show that galactinol content of mature dry seed can be used as a biomarker for seed longevity in Brassicaceae and tomato. PMID:26993241

  3. 78 FR 78165 - Orders: Reporting by Regulated Entities of Stress Testing Results as of September 30, 2013...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-12-26

    ... September 26, 2013, at 78 FR 59219. FHFA also is amending the Summary Instructions and Guidance, which... AGENCY 12 CFR Part 1238 Orders: Reporting by Regulated Entities of Stress Testing Results as of September... prescribe for the regulated entities the scenarios to be used for stress testing. The Summary...

  4. Transcriptionally and post-transcriptionally regulated microRNAs in heat stress response in barley

    PubMed Central

    Kruszka, Katarzyna; Pacak, Andrzej; Swida-Barteczka, Aleksandra; Nuc, Przemyslaw; Alaba, Sylwia; Wroblewska, Zuzanna; Karlowski, Wojciech; Jarmolowski, Artur; Szweykowska-Kulinska, Zofia

    2014-01-01

    Heat stress is one of the major abiotic factors that can induce severe plant damage, leading to a decrease in crop plant productivity. Despite barley being a cereal of great economic importance, few data are available concerning its thermotolerance mechanisms. In this work microRNAs (miRNAs) involved in heat stress response in barley were investigated. The level of selected barley mature miRNAs was examined by hybridization. Quantitative real-time PCR (RT-qPCR) was used to monitor the changes in the expression profiles of primary miRNA (pri-miRNA) precursors, as well as novel and conserved target genes during heat stress. The miRNA-mediated cleavage sites in the target transcripts were confirmed by degradome analysis and the 5’ RACE (rapid amplification of cDNA ends) approach. Four barley miRNAs (miR160a, 166a, 167h, and 5175a) were found which are heat stress up-regulated at the level of both mature miRNAs and precursor pri-miRNAs. Moreover, the splicing of introns hosting miR160a and miR5175a is also heat induced. The results demonstrate transcriptional and post-transcriptional regulation of heat-responsive miRNAs in barley. The observed induction of miRNA expression is correlated with the down-regulation of the expression level of their experimentally identified new and conservative target genes. PMID:25183744

  5. AtMYB12 regulates flavonoids accumulation and abiotic stress tolerance in transgenic Arabidopsis thaliana.

    PubMed

    Wang, Feibing; Kong, Weili; Wong, Gary; Fu, Lifeng; Peng, Rihe; Li, Zhenjun; Yao, Quanhong

    2016-08-01

    In plants, transcriptional regulation is the most important tool for modulating flavonoid biosynthesis. The AtMYB12 gene from Arabidopsis thaliana has been shown to regulate the expression of key enzyme genes involved in flavonoid biosynthesis, leading to the increased accumulation of flavonoids. In this study, the codon-optimized AtMYB12 gene was chemically synthesized. Subcellular localization analysis in onion epidermal cells indicated that AtMYB12 was localized to the nucleus. Its overexpression significantly increased accumulation of flavonoids and enhanced salt and drought tolerance in transgenic Arabidopsis plants. Real-time quantitative PCR (qRT-PCR) analysis showed that overexpression of AtMYB12 resulted in the up-regulation of genes involved in flavonoid biosynthesis, abscisic acid (ABA) biosynthesis, proline biosynthesis, stress responses and ROS scavenging under salt and drought stresses. Further analyses under salt and drought stresses showed significant increases of ABA, proline content, superoxide dismutase (SOD) and peroxidase (POD) activities, as well as significant reduction of H2O2 and malonaldehyde (MDA) content. The results demonstrate the explicit role of AtMYB12 in conferring salt and drought tolerance by increasing the levels of flavonoids and ABA in transgenic Arabidopsis. The AtMYB12 gene has the potential to be used to enhance tolerance to abiotic stresses in plants. PMID:27033553

  6. Diacylglycerol kinase regulation of protein kinase D during oxidative stress-induced intestinal cell injury

    SciTech Connect

    Song Jun; Li Jing; Mourot, Joshua M.; Mark Evers, B.; Chung, Dai H.

    2008-10-17

    We recently demonstrated that protein kinase D (PKD) exerts a protective function during oxidative stress-induced intestinal epithelial cell injury; however, the exact role of DAG kinase (DGK){zeta}, an isoform expressed in intestine, during this process is unknown. We sought to determine the role of DGK during oxidative stress-induced intestinal cell injury and whether DGK acts as an upstream regulator of PKD. Inhibition of DGK with R59022 compound or DGK{zeta} siRNA transfection decreased H{sub 2}O{sub 2}-induced RIE-1 cell apoptosis as measured by DNA fragmentation and increased PKD phosphorylation. Overexpression of kinase-dead DGK{zeta} also significantly increased PKD phosphorylation. Additionally, endogenous nuclear DGK{zeta} rapidly translocated to the cytoplasm following H{sub 2}O{sub 2} treatment. Our findings demonstrate that DGK is involved in the regulation of oxidative stress-induced intestinal cell injury. PKD activation is induced by DGK{zeta}, suggesting DGK is an upstream regulator of oxidative stress-induced activation of the PKD signaling pathway in intestinal epithelial cells.

  7. Regulation of potassium transport in plants under hostile conditions: implications for abiotic and biotic stress tolerance.

    PubMed

    Shabala, Sergey; Pottosin, Igor

    2014-07-01

    Intracellular potassium homeostasis is a prerequisite for the optimal operation of plant metabolic machinery and plant's overall performance. It is controlled by K(+) uptake, efflux and intracellular and long-distance relocation, mediated by a large number of K(+) -selective and non-selective channels and transporters located at both plasma and vacuolar membranes. All abiotic and biotic stresses result in a significant disturbance to intracellular potassium homeostasis. In this work, we discuss molecular mechanisms and messengers mediating potassium transport and homeostasis focusing on four major environmental stresses: salinity, drought, flooding and biotic factors. We argue that cytosolic K(+) content may be considered as one of the 'master switches' enabling plant transition from the normal metabolism to 'hibernated state' during first hours after the stress exposure and then to a recovery phase. We show that all these stresses trigger substantial disturbance to K(+) homeostasis and provoke a feedback control on K(+) channels and transporters expression and post-translational regulation of their activity, optimizing K(+) absorption and usage, and, at the extreme end, assisting the programmed cell death. We discuss specific modes of regulation of the activity of K(+) channels and transporters by membrane voltage, intracellular Ca(2+) , reactive oxygen species, polyamines, phytohormones and gasotransmitters, and link this regulation with plant-adaptive responses to hostile environments. PMID:24506225

  8. Conserved versatile master regulators in signalling pathways in response to stress in plants

    PubMed Central

    Balderas-Hernández, Victor E.; Alvarado-Rodríguez, Miguel; Fraire-Velázquez, Saúl

    2013-01-01

    From the first land plants to the complex gymnosperms and angiosperms of today, environmental conditions have forced plants to develop molecular strategies to surpass natural obstacles to growth and proliferation, and these genetic gains have been transmitted to the following generations. In this long natural process, novel and elaborate mechanisms have evolved to enable plants to cope with environmental limitations. Elements in many signalling cascades enable plants to sense different, multiple and simultaneous ambient cues. A group of versatile master regulators of gene expression control plant responses to stressing conditions. For crop breeding purposes, the task is to determine how to activate these key regulators to enable accurate and optimal reactions to common stresses. In this review, we discuss how plants sense biotic and abiotic stresses, how and which master regulators are implied in the responses to these stresses, their evolution in the life kingdoms, and the domains in these proteins that interact with other factors to lead to a proper and efficient plant response. PMID:24147216

  9. Identification of a Novel Endoplasmic Reticulum Stress Response Element Regulated by XBP1*

    PubMed Central

    Misiewicz, Michael; Déry, Marc-André; Foveau, Bénédicte; Jodoin, Julie; Ruths, Derek; LeBlanc, Andréa C.

    2013-01-01

    Understanding the regulatory mechanisms mediating PRNP gene expression is highly relevant to elucidating normal cellular prion protein (PrP) function(s) and the transmissibility of prion protein neurodegenerative diseases. Here, luciferase reporter assays showed that an endoplasmic reticulum stress element (ERSE)-like element, CCAAT-N26-CCACG in the human PRNP promoter, is regulated by ER stress and X-box-binding protein 1 (XBP1) but not by activating transcription factor 6 α (ATF6α). Bioinformatics identified the ERSE-26 motif in 37 other human genes in the absence of canonical ERSE sites except for three genes. Several of these genes are associated with a synaptic function or are involved in oxidative stress. Brefeldin A, tunicamycin, and thapsigargin ER stressors induced gene expression of PRNP and four randomly chosen ERSE-26-containing genes, ERLEC1, GADD45B, SESN2, and SLC38A5, in primary human neuron cultures or in the breast carcinoma MCF-7 cell line, although the level of the response depends on the gene analyzed, the genetic background of the cells, the cell type, and the ER stressor. Overexpression of XBP1 increased, whereas siRNA knockdown of XBP1 considerably reduced, PRNP and ERLEC1 mRNA levels in MCF-7 cells. Taken together, these results identify a novel ER stress regulator, which implicates the ER stress response in previously unrecognized cellular functions. PMID:23737521

  10. Conservation of thiol-oxidative stress responses regulated by SigR orthologues in actinomycetes

    PubMed Central

    Kim, Min-Sik; Dufour, Yann S.; Yoo, Ji Sun; Cho, Yoo-Bok; Park, Joo-Hong; Nam, Gi-Baeg; Kim, Hae Min; Lee, Kang-Lok; Donohue, Timothy J.; Roe, Jung-Hye

    2015-01-01

    Summary Numerous thiol-reactive compounds cause oxidative stress where cells counteract by activation of survival strategies regulated by thiol-based sensors. In Streptomyces coelicolor, a model actinomycete, a sigma/antisigma pair SigR/RsrA controls the response to thiol-oxidative stress. To unravel its full physiological functions, chromatin immuno-precipitation combined with sequence and transcript analyses were employed to identify 108 SigR target genes in S. coelicolor and to predict orthologous regulons across actinomycetes. In addition to reported genes for thiol homeostasis, protein degradation and ribosome modulation, 64 additional operons were identified suggesting new functions of this global regulator. We demonstrate that SigR maintains the level and activity of the housekeeping sigma factor HrdB during thiol-oxidative stress, a novel strategy for stress responses. We also found that SigR defends cells against UV and thiol-reactive damages, in which repair UvrA takes a part. Using a refined SigR-binding sequence model, SigR orthologues and their targets were predicted in 42 actinomycetes. This revealed a conserved core set of SigR targets to function for thiol homeostasis, protein quality control, possible modulation of transcription and translation, flavin-mediated redox reactions, and Fe-S delivery. The composition of the SigR regulon reveals a robust conserved physiological mechanism to deal with thiol-oxidative stress from bacteria to human. PMID:22651816

  11. LncRNA NBR2 engages a metabolic checkpoint by regulating AMPK under energy stress.

    PubMed

    Liu, Xiaowen; Xiao, Zhen-Dong; Han, Leng; Zhang, Jiexin; Lee, Szu-Wei; Wang, Wenqi; Lee, Hyemin; Zhuang, Li; Chen, Junjie; Lin, Hui-Kuan; Wang, Jing; Liang, Han; Gan, Boyi

    2016-04-01

    Long non-coding RNAs (lncRNAs) have emerged as critical regulators in various cellular processes. However, the potential involvement of lncRNAs in kinase signalling remains largely unknown. AMP-activated protein kinase (AMPK) acts as a critical sensor of cellular energy status. Here we show that the lncRNA NBR2 (neighbour of BRCA1 gene 2) is induced by the LKB1-AMPK pathway under energy stress. On energy stress, NBR2 in turn interacts with AMPK and promotes AMPK kinase activity, thus forming a feed-forward loop to potentiate AMPK activation during energy stress. Depletion of NBR2 attenuates energy-stress-induced AMPK activation, resulting in unchecked cell cycling, altered apoptosis/autophagy response, and increased tumour development in vivo. NBR2 is downregulated and its low expression correlates with poor clinical outcomes in some human cancers. Together, the results of our study uncover a mechanism coupling lncRNAs with metabolic stress response, and provides a broad framework to understand further the regulation of kinase signalling by lncRNAs. PMID:26999735

  12. Regulation of Nitrite Stress Response in Desulfovibrio vulgaris Hildenborough, a Model Sulfate-Reducing Bacterium

    PubMed Central

    Rajeev, Lara; Chen, Amy; Kazakov, Alexey E.; Luning, Eric G.; Zane, Grant M.; Novichkov, Pavel S.; Wall, Judy D.

    2015-01-01

    ABSTRACT Sulfate-reducing bacteria (SRB) are sensitive to low concentrations of nitrite, and nitrite has been used to control SRB-related biofouling in oil fields. Desulfovibrio vulgaris Hildenborough, a model SRB, carries a cytochrome c-type nitrite reductase (nrfHA) that confers resistance to low concentrations of nitrite. The regulation of this nitrite reductase has not been directly examined to date. In this study, we show that DVU0621 (NrfR), a sigma54-dependent two-component system response regulator, is the positive regulator for this operon. NrfR activates the expression of the nrfHA operon in response to nitrite stress. We also show that nrfR is needed for fitness at low cell densities in the presence of nitrite because inactivation of nrfR affects the rate of nitrite reduction. We also predict and validate the binding sites for NrfR upstream of the nrfHA operon using purified NrfR in gel shift assays. We discuss possible roles for NrfR in regulating nitrate reductase genes in nitrate-utilizing Desulfovibrio spp. IMPORTANCE The NrfA nitrite reductase is prevalent across several bacterial phyla and required for dissimilatory nitrite reduction. However, regulation of the nrfA gene has been studied in only a few nitrate-utilizing bacteria. Here, we show that in D. vulgaris, a bacterium that does not respire nitrate, the expression of nrfHA is induced by NrfR upon nitrite stress. This is the first report of regulation of nrfA by a sigma54-dependent two-component system. Our study increases our knowledge of nitrite stress responses and possibly of the regulation of nitrate reduction in SRB. PMID:26283774

  13. The Campylobacter jejuni Ferric Uptake Regulator Promotes Acid Survival and Cross-Protection against Oxidative Stress.

    PubMed

    Askoura, Momen; Sarvan, Sabina; Couture, Jean-François; Stintzi, Alain

    2016-05-01

    Campylobacter jejuni is a prevalent cause of bacterial gastroenteritis in humans worldwide. The mechanisms by which C. jejuni survives stomach acidity remain undefined. In the present study, we demonstrated that the C. jejuni ferric uptake regulator (Fur) plays an important role in C. jejuni acid survival and acid-induced cross-protection against oxidative stress. A C. jejuni Δfur mutant was more sensitive to acid than the wild-type strain. Profiling of the acid stimulon of the C. jejuni Δfur mutant allowed us to uncover Fur-regulated genes under acidic conditions. In particular, Fur was found to upregulate genes involved in flagellar and cell envelope biogenesis upon acid stress, and mutants with deletions of these genes were found to be defective in surviving acid stress. Interestingly, prior acid exposure of C. jejuni cross-protected against oxidative stress in a catalase (KatA)- and Fur-dependent manner. Western blotting and reverse transcription-quantitative PCR revealed increased expression of KatA upon acid stress. Electrophoretic mobility shift assays (EMSAs) demonstrated that the binding affinity between Fur and the katA promoter is reduced in vitro under conditions of low pH, rationalizing the higher levels of expression of katA under acidic conditions. Strikingly, the Δfur mutant exhibited reduced virulence in both human epithelial cells and the Galleria mellonella infection model. Altogether, this is the first study showing that, in addition to its role in iron metabolism, Fur is an important regulator of C. jejuni acid responses and this function cross-protects against oxidative stress. Moreover, our results clearly demonstrate Fur's important role in C. jejuni pathogenesis. PMID:26883589

  14. The role of glutathione in the regulation of nucleotide excision repair during oxidative stress.

    PubMed

    Langie, Sabine A S; Knaapen, Ad M; Houben, Joyce M J; van Kempen, Frederik C; de Hoon, Joep P J; Gottschalk, Ralph W H; Godschalk, Roger W L; van Schooten, Frederik J

    2007-02-01

    Nucleotide excision repair (NER) mainly repairs bulky DNA adducts and helix distorting lesions, but is additionally considered to be a back-up system for base excision repair to remove oxidative stress induced DNA damage. Therefore, it can be speculated that NER is up-regulated or primed by oxidative stress. Exposure of human pulmonary epithelial cells (A549) to non-toxic doses of 100muM H(2)O(2) indeed showed a 2 to 4.5-fold increase in expression of XPA, XPC, ERCC4, and ERCC5, whereas the expression of ERCC1 was 5-fold decreased. Phenotypical assessment of NER capacity (i.e. recognition and incision of benzo[a]pyrene-DNA adducts) showed a significant decrease to less than 50% after H(2)O(2) exposure, which paralleled the effects of H(2)O(2) on ERCC1 expression. To study the possible involvement of glutathione (GSH) in the regulation of NER, cells were pre-incubated with 0.5mM BSO, resulting in total GSH depletion and increased intracellular oxidative stress. In GSH-depleted cells, the down-regulation of ERCC1 expression by H(2)O(2) was completely abolished and the up-regulation of ERCC4 expression was potentiated from 2.5-fold to >10-fold. Similarly, the H(2)O(2)-induced decrease in NER capacity was absent in GSH-depleted cells. Overall, our data suggest that NER capacity as well as the expression of NER related genes can be modulated by oxidative stress. ERCC1 expression and NER capacity correlated strongly (R(2)=0.85, P<0.01) after oxidant exposure, indicating ERCC1 as a specific target for oxidative stress induced modification of NER. PMID:17207589

  15. Regulation of bovine pyruvate carboxylase mRNA and promoter expression by thermal stress.

    PubMed

    White, H M; Koser, S L; Donkin, S S

    2012-09-01

    Pyruvate carboxylase (PC) catalyzes the rate-limiting step in gluconeogenesis from lactate and is a determinant of tricarboxylic acid cycle carbon flux. Bovine PC 5' untranslated region (UTR) mRNA variants are the products of a single PC gene containing 3 promoter regions (P3, P2, and P1, 5' to 3') that are responsive to physiological and nutritional stressors. The objective of this study was to determine the direct effects of thermal stress on PC mRNA and gene expression in bovine hepatocyte monolayer cultures, rat hepatoma (H4IIE) cells, and Madin-Darby bovine kidney epithelial (MDBK) cells. Hepatocytes were isolated from 3 Holstein bull calves and used to prepare monolayer cultures. Rat hepatoma cells and MDBK cells were obtained from American Type Culture Collection, Manassas, VA. Beginning 24 h after initial seeding, cells were subjected to either 37°C (control) or 42°C (thermal stress) for 24 h. Treatments were applied in triplicate in a minimum of 3 independent cell preparations. For bovine primary hepatocytes, endogenous expression of bovine PC mRNA increased (P < 0.1) with 24 h of thermal stress (1.31 vs. 2.79 ± 0.49, arbitrary units, control vs. thermal stress, respectively), but there was no change (P ≥ 0.1) in cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) mRNA expression. Similarly, exposure of MDBK cells to thermal stress increased (P < 0.1) expression of bovine PC mRNA without altering (P ≥ 0.1) PEPCK-C mRNA expression. Conversely, there was no effect (P ≥ 0.1) of thermal stress on endogenous rat PC (0.47 vs. 0.30 ± 0.08, control vs. thermal stress) or PEPCK-C (1.61 vs. 1.20 ± 0.48, arbitrary units, control vs. thermal stress, respectively) mRNA expressions in H4IIE cells. To further investigate the regulation of PC, H4IIE cells were transiently transfected with bovine promoter-luciferase constructs containing either P1, P2, or P3, and exposed to thermal stress for 23 h. Activity of P1 was suppressed (P < 0.1) 5-fold, activity of P2

  16. CIRCADIAN CLOCK-ASSOCIATED 1 regulates ROS homeostasis and oxidative stress responses

    PubMed Central

    Lai, Alvina Grace; Doherty, Colleen J.; Mueller-Roeber, Bernd; Kay, Steve A.; Schippers, Jos H. M.; Dijkwel, Paul P.

    2012-01-01

    Organisms have evolved endogenous biological clocks as internal timekeepers to coordinate metabolic processes with the external environment. Here, we seek to understand the mechanism of synchrony between the oscillator and products of metabolism known as Reactive Oxygen Species (ROS) in Arabidopsis thaliana. ROS-responsive genes exhibit a time-of-day–specific phase of expression under diurnal and circadian conditions, implying a role of the circadian clock in transcriptional regulation of these genes. Hydrogen peroxide production and scavenging also display time-of-day phases. Mutations in the core-clock regulator, CIRCADIAN CLOCK ASSOCIATED 1 (CCA1), affect the transcriptional regulation of ROS-responsive genes, ROS homeostasis, and tolerance to oxidative stress. Mis-expression of EARLY FLOWERING 3, LUX ARRHYTHMO, and TIMING OF CAB EXPRESSION 1 affect ROS production and transcription, indicating a global effect of the clock on the ROS network. We propose CCA1 as a master regulator of ROS homeostasis through association with the Evening Element in promoters of ROS genes in vivo to coordinate time-dependent responses to oxidative stress. We also find that ROS functions as an input signal that affects the transcriptional output of the clock, revealing an important link between ROS signaling and circadian output. Temporal coordination of ROS signaling by CCA1 and the reciprocal control of circadian output by ROS reveal a mechanistic link that allows plants to master oxidative stress responses. PMID:23027948

  17. EXB1/WRKY71 transcription factor regulates both shoot branching and responses to abiotic stresses.

    PubMed

    Guo, Dongshu; Qin, Genji

    2016-03-01

    As the sessile organisms, plants evolve different strategies to survive in adverse environmental conditions. The elaborate regulation of shoot branching is an important strategy for plant morphological adaptation to various environments, while the regulation of reactive oxygen species (ROS), salicylic acid (SA) and jasmonic acid (JA) is pivotal for plant responses to biotic and abiotic stresses. Recently, we have demonstrated that Arabidopsis EXB1, a WRKY transcription factor, is a positive regulator of shoot branching as a cover story in Plant Cell. Here we show that WRKY23, an EXB1 close member, has a redundant role in control of shoot branching. We further show that EXB1 is induced by H2O2, ABA or mannitol treatments, suggesting that EXB1 may also play roles in plant responses to abiotic stresses. RNA-sequencing (RNA-seq) analysis using 4EnhpEXB1-EXB1GR inducible line indicates that the genes involved in oxidative stress, oxidation reduction, SA or JA signaling pathway are regulated by EXB1 induction in a short time. We suggest that EXB1/WRKY71 transcription factor may play pivotal roles in plant adaptation to environments by both morphological and physiological ways. PMID:26914912

  18. Longevity and GAPDH Stability in Bivalves and Mammals: A Convenient Marker for Comparative Gerontology and Proteostasis

    PubMed Central

    Treaster, Stephen B.; Chaudhuri, Asish R.; Austad, Steven N.

    2015-01-01

    Background Comparative aging studies, particularly those that include species of exceptional resistance to aging processes, can potentially illuminate novel senescence-retarding mechanisms. In recent years, protein homeostasis (proteostasis) has been implicated in fundamental aging processes. Here we further evaluate the relationship between proteostasis and longevity in a selection of bivalve mollusks and mammals with maximum longevities ranging from 3 to 507 years. Methods & Results We experimentally examined proteostasis using glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as a reporter, as it is ubiquitously expressed, highly conserved, and conveniently assayed. The ability to maintain this enzymatic function was tested with increasing concentrations of the chaotropic agent urea, revealing a robust relationship with longevity in bivalves and mice. While our shortest-lived mollusk and mouse lost all activity by 2.5 and 3.5 M urea respectively, the longest-lived mollusk species, Arctica islandica, still preserved 45% of its basal function even at 6 M urea. To confirm that GAPDH proteostasis has a broad association with longevity, we also investigated a selection of primate species ranging in maximum longevity from 22 to 122 years. They outperformed the mouse at all concentrations, but among the primates results were variable at low urea doses. Still, at 6 M urea baboon and human samples retained 10% of their activity while both mouse and marmoset samples had no activity. Mechanism of Exceptional Stress Resistance To explore possible mechanisms of the exceptional stress resistance of A. islandica GAPDH we enzymatically removed post-translational glycosylation, but observed no decrease in stability. We also removed molecules smaller than 30 kDa, which includes most small heat shock proteins, but again did not compromise the exceptional stress resistance of Arctica GAPDH. Conclusion While the mechanism underlying A. islandica’s exceptional stress resistance

  19. Oxidative stress in the haematopoietic niche regulates the cellular immune response in Drosophila.

    PubMed

    Sinenko, Sergey A; Shim, Jiwon; Banerjee, Utpal

    2012-01-01

    Oxidative stress induced by high levels of reactive oxygen species (ROS) is associated with the development of different pathological conditions, including cancers and autoimmune diseases. We analysed whether oxidatively challenged tissue can have systemic effects on the development of cellular immune responses using Drosophila as a model system. Indeed, the haematopoietic niche that normally maintains blood progenitors can sense oxidative stress and regulate the cellular immune response. Pathogen infection induces ROS in the niche cells, resulting in the secretion of an epidermal growth factor-like cytokine signal that leads to the differentiation of specialized cells involved in innate immune responses. PMID:22134547

  20. The Caenorhabditis elegans Myc-Mondo/Mad Complexes Integrate Diverse Longevity Signals

    PubMed Central

    Johnson, David W.; Llop, Jesse R.; Farrell, Sara F.; Yuan, Jie; Stolzenburg, Lindsay R.; Samuelson, Andrew V.

    2014-01-01

    The Myc family of transcription factors regulates a variety of biological processes, including the cell cycle, growth, proliferation, metabolism, and apoptosis. In Caenorhabditis elegans, the “Myc interaction network” consists of two opposing heterodimeric complexes with antagonistic functions in transcriptional control: the Myc-Mondo:Mlx transcriptional activation complex and the Mad:Max transcriptional repression complex. In C. elegans, Mondo, Mlx, Mad, and Max are encoded by mml-1, mxl-2, mdl-1, and mxl-1, respectively. Here we show a similar antagonistic role for the C. elegans Myc-Mondo and Mad complexes in longevity control. Loss of mml-1 or mxl-2 shortens C. elegans lifespan. In contrast, loss of mdl-1 or mxl-1 increases longevity, dependent upon MML-1:MXL-2. The MML-1:MXL-2 and MDL-1:MXL-1 complexes function in both the insulin signaling and dietary restriction pathways. Furthermore, decreased insulin-like/IGF-1 signaling (ILS) or conditions of dietary restriction increase the accumulation of MML-1, consistent with the notion that the Myc family members function as sensors of metabolic status. Additionally, we find that Myc family members are regulated by distinct mechanisms, which would allow for integrated control of gene expression from diverse signals of metabolic status. We compared putative target genes based on ChIP-sequencing data in the modENCODE project and found significant overlap in genomic DNA binding between the major effectors of ILS (DAF-16/FoxO), DR (PHA-4/FoxA), and Myc family (MDL-1/Mad/Mxd) at common target genes, which suggests that diverse signals of metabolic status converge on overlapping transcriptional programs that influence aging. Consistent with this, there is over-enrichment at these common targets for genes that function in lifespan, stress response, and carbohydrate metabolism. Additionally, we find that Myc family members are also involved in stress response and the maintenance of protein homeostasis. Collectively

  1. The Influence of Work-Related Chronic Stress on the Regulation of Emotion and on Functional Connectivity in the Brain

    PubMed Central

    Golkar, Armita; Johansson, Emilia; Kasahara, Maki; Osika, Walter; Perski, Aleksander; Savic, Ivanka

    2014-01-01

    Despite mounting reports about the negative effects of chronic occupational stress on cognitive and emotional functions, the underlying mechanisms are unknown. Recent findings from structural MRI raise the question whether this condition could be associated with a functional uncoupling of the limbic networks and an impaired modulation of emotional stress. To address this, 40 subjects suffering from burnout symptoms attributed to chronic occupational stress and 70 controls were investigated using resting state functional MRI. The participants' ability to up- regulate, down-regulate, and maintain emotion was evaluated by recording their acoustic startle response while viewing neutral and negatively loaded images. Functional connectivity was calculated from amygdala seed regions, using explorative linear correlation analysis. Stressed subjects were less capable of down-regulating negative emotion, but had normal acoustic startle responses when asked to up-regulate or maintain emotion and when no regulation was required. The functional connectivity between the amygdala and the anterior cingulate cortex correlated with the ability to down-regulate negative emotion. This connectivity was significantly weaker in the burnout group, as was the amygdala connectivity with the dorsolateral prefrontal cortex and the motor cortex, whereas connectivity from the amygdala to the cerebellum and the insular cortex were stronger. In subjects suffering from chronic occupational stress, the functional couplings within the emotion- and stress-processing limbic networks seem to be altered, and associated with a reduced ability to down-regulate the response to emotional stress, providing a biological substrate for a further facilitation of the stress condition. PMID:25184294

  2. The influence of work-related chronic stress on the regulation of emotion and on functional connectivity in the brain.

    PubMed

    Golkar, Armita; Johansson, Emilia; Kasahara, Maki; Osika, Walter; Perski, Aleksander; Savic, Ivanka

    2014-01-01

    Despite mounting reports about the negative effects of chronic occupational stress on cognitive and emotional functions, the underlying mechanisms are unknown. Recent findings from structural MRI raise the question whether this condition could be associated with a functional uncoupling of the limbic networks and an impaired modulation of emotional stress. To address this, 40 subjects suffering from burnout symptoms attributed to chronic occupational stress and 70 controls were investigated using resting state functional MRI. The participants' ability to up- regulate, down-regulate, and maintain emotion was evaluated by recording their acoustic startle response while viewing neutral and negatively loaded images. Functional connectivity was calculated from amygdala seed regions, using explorative linear correlation analysis. Stressed subjects were less capable of down-regulating negative emotion, but had normal acoustic startle responses when asked to up-regulate or maintain emotion and when no regulation was required. The functional connectivity between the amygdala and the anterior cingulate cortex correlated with the ability to down-regulate negative emotion. This connectivity was significantly weaker in the burnout group, as was the amygdala connectivity with the dorsolateral prefrontal cortex and the motor cortex, whereas connectivity from the amygdala to the cerebellum and the insular cortex were stronger. In subjects suffering from chronic occupational stress, the functional couplings within the emotion- and stress-processing limbic networks seem to be altered, and associated with a reduced ability to down-regulate the response to emotional stress, providing a biological substrate for a further facilitation of the stress condition. PMID:25184294

  3. Helping DC Plan Participants Hedge Longevity Risk.

    PubMed

    Rafaloff, Roberta

    2016-01-01

    To help retirees turn savings into a steady, permanent income stream they won't outlive, the U.S. Treasury Department has made it easier for defined contribution plans to offer qualifying longevity annuity contracts (QLACs). This article explains the features of QLACs and why both employees and employers are finding this type of insurance an attractive option, as it protects people against their greatest risk in retirement--longevity. The author provides five steps a plan sponsor needs to take to add a QLAC. PMID:27017797

  4. WRKY Proteins: Signaling and Regulation of Expression during Abiotic Stress Responses

    PubMed Central

    Banerjee, Aditya

    2015-01-01

    WRKY proteins are emerging players in plant signaling and have been thoroughly reported to play important roles in plants under biotic stress like pathogen attack. However, recent advances in this field do reveal the enormous significance of these proteins in eliciting responses induced by abiotic stresses. WRKY proteins act as major transcription factors, either as positive or negative regulators. Specific WRKY factors which help in the expression of a cluster of stress-responsive genes are being targeted and genetically modified to induce improved abiotic stress tolerance in plants. The knowledge regarding the signaling cascade leading to the activation of the WRKY proteins, their interaction with other proteins of the signaling pathway, and the downstream genes activated by them are altogether vital for justified targeting of the WRKY genes. WRKY proteins have also been considered to generate tolerance against multiple abiotic stresses with possible roles in mediating a cross talk between abiotic and biotic stress responses. In this review, we have reckoned the diverse signaling pattern and biological functions of WRKY proteins throughout the plant kingdom along with the growing prospects in this field of research. PMID:25879071

  5. Impaired endothelial shear stress induces podosome assembly via VEGF up-regulation.

    PubMed

    Fey, Theres; Schubert, Kai Michael; Schneider, Holger; Fein, Evelyn; Kleinert, Eike; Pohl, Ulrich; Dendorfer, Andreas

    2016-08-01

    Podosomes are dynamic cytoskeletal membrane structures with local adhesive and proteolytic activity. They are critically involved in angiogenesis and vascular adaptive growth. Here, we studied in HUVECs and murine small vessels whether shear stress controls podosome assembly and local proteolytic activity. Podosomes were characterized by immunohistochemistry, and their proteolytic activity was assessed as degradation imprints in fluorescent gelatin that was used as growth substrate. Compared with controls (10 dyn/cm(2)), the number of podosomes formed per time was doubled when cells were exposed to low shear stress (0.3 dyn/cm(2)) or even increased 5-fold under static conditions. This was a result of an enhanced expression of VEGF after reduction of shear stress. Consequently, enhanced podosome formation could be prevented by a VEGF receptor antagonist as well by interruption of VEGF signaling via inhibition of PI3K, Src, or p38. Increase of podosome assembly went along with significantly augmented cell motility. In vivo experiments in mouse arteries confirmed increased endothelial podosome numbers when shear stress was abolished by vessel occlusion. We conclude that shear stress, by reducing VEGF release, inhibits podosome assembly. Hence, endothelial cell-mediated matrix proteolysis and migratory activity are inhibited, thereby stabilizing the structure of the vessel wall.-Fey, T., Schubert, K. M., Schneider, H., Fein, E., Kleinert, E., Pohl, U., Dendorfer, A. Impaired endothelial shear stress induces podosome assembly via VEGF up-regulation. PMID:27103579

  6. Abiotic Stresses: Insight into Gene Regulation and Protein Expression in Photosynthetic Pathways of Plants.

    PubMed

    Nouri, Mohammad-Zaman; Moumeni, Ali; Komatsu, Setsuko

    2015-01-01

    Global warming and climate change intensified the occurrence and severity of abiotic stresses that seriously affect the growth and development of plants,especially, plant photosynthesis. The direct impact of abiotic stress on the activity of photosynthesis is disruption of all photosynthesis components such as photosystem I and II, electron transport, carbon fixation, ATP generating system and stomatal conductance. The photosynthetic system of plants reacts to the stress differently, according to the plant type, photosynthetic systems (C₃ or C₄), type of the stress, time and duration of the occurrence and several other factors. The plant responds to the stresses by a coordinate chloroplast and nuclear gene expression. Chloroplast, thylakoid membrane, and nucleus are the main targets of regulated proteins and metabolites associated with photosynthetic pathways. Rapid responses of plant cell metabolism and adaptation to photosynthetic machinery are key factors for survival of plants in a fluctuating environment. This review gives a comprehensive view of photosynthesis-related alterations at the gene and protein levels for plant adaptation or reaction in response to abiotic stress. PMID:26343644

  7. p53 and Translation Attenuation Regulate Distinct Cell Cycle Checkpoints during Endoplasmic Reticulum (ER) Stress*

    PubMed Central

    Thomas, Sally E.; Malzer, Elke; Ordóñez, Adriana; Dalton, Lucy E.; van ′t Wout, Emily F. A.; Liniker, Elizabeth; Crowther, Damian C.; Lomas, David A.; Marciniak, Stefan J.

    2013-01-01

    Cell cycle checkpoints ensure that proliferation occurs only under permissive conditions, but their role in linking nutrient availability to cell division is incompletely understood. Protein folding within the endoplasmic reticulum (ER) is exquisitely sensitive to energy supply and amino acid sources because deficiencies impair luminal protein folding and consequently trigger ER stress signaling. Following ER stress, many cell types arrest within the G1 phase, although recent studies have identified a novel ER stress G2 checkpoint. Here, we report that ER stress affects cell cycle progression via two classes of signal: an early inhibition of protein synthesis leading to G2 delay involving CHK1 and a later induction of G1 arrest associated both with the induction of p53 target genes and loss of cyclin D1. We show that substitution of p53/47 for p53 impairs the ER stress G1 checkpoint, attenuates the recovery of protein translation, and impairs induction of NOXA, a mediator of cell death. We propose that cell cycle regulation in response to ER stress comprises redundant pathways invoked sequentially first to impair G2 progression prior to ultimate G1 arrest. PMID:23341460

  8. Abiotic Stresses: Insight into Gene Regulation and Protein Expression in Photosynthetic Pathways of Plants

    PubMed Central

    Nouri, Mohammad-Zaman; Moumeni, Ali; Komatsu, Setsuko

    2015-01-01

    Global warming and climate change intensified the occurrence and severity of abiotic stresses that seriously affect the growth and development of plants, especially, plant photosynthesis. The direct impact of abiotic stress on the activity of photosynthesis is disruption of all photosynthesis components such as photosystem I and II, electron transport, carbon fixation, ATP generating system and stomatal conductance. The photosynthetic system of plants reacts to the stress differently, according to the plant type, photosynthetic systems (C3 or C4), type of the stress, time and duration of the occurrence and several other factors. The plant responds to the stresses by a coordinate chloroplast and nuclear gene expression. Chloroplast, thylakoid membrane, and nucleus are the main targets of regulated proteins and metabolites associated with photosynthetic pathways. Rapid responses of plant cell metabolism and adaptation to photosynthetic machinery are key factors for survival of plants in a fluctuating environment. This review gives a comprehensive view of photosynthesis-related alterations at the gene and protein levels for plant adaptation or reaction in response to abiotic stress. PMID:26343644

  9. Regulation of Pol III Transcription by Nutrient and Stress Signaling Pathways

    PubMed Central

    Moir, Robyn D.; Willis, Ian M.

    2012-01-01

    Transcription by RNA polymerase III (pol III) is responsible for ~15% of total cellular transcription through the generation of small structured RNAs such as tRNA and 5S RNA. The coordinate synthesis of these molecules with ribosomal protein mRNAs and rRNA couples the production of ribosomes and their tRNA substrates and balances protein synthetic capacity with the growth requirements of the cell. Ribosome biogenesis in general and pol III transcription in particular is known to be regulated by nutrient availability, cell stress and cell cycle stage and is perturbed in pathological states. High throughput proteomic studies have catalogued modifications to pol III subunits, assembly, initiation and accessory factors but most of these modifications have yet to be linked to functional consequences. Here we review our current understanding of the major points of regulation in the pol III transcription apparatus, the targets of regulation and the signaling pathways known to regulate their function. PMID:23165150

  10. RNA helicase SACY-1 is required for longevity caused by various genetic perturbations in Caenorhabditis elegans.

    PubMed

    Seo, Mihwa; Park, Sangsoon; Nam, Hong Gil; Lee, Seung-Jae V

    2016-07-17

    RNA helicases, which unwind RNAs, are essential for RNA metabolism and homeostasis. However, the roles of RNA helicases in specific physiological processes remain poorly understood. We recently reported that an RNA helicase, HEL-1, promotes long lifespan conferred by reduced insulin/insulin-like growth factor-1 (IGF-1) signaling (IIS) in Caenorhabditis elegans. We also showed that HEL-1 induces the expression of longevity genes by physically interacting with Forkhead box O (FOXO) transcription factor. Thus, the HEL-1 RNA helicase appears to regulate lifespan by specifically activating FOXO in IIS. In the current study, we report another longevity-promoting RNA helicase, Suppressor of ACY-4 sterility 1 (SACY-1). SACY-1 contributed to the longevity of daf-2/insulin/IGF-1 receptor mutants. Unlike HEL-1, SACY-1 was also required for the longevity due to mutations in genes involved in non-IIS pathways. Thus, SACY-1 appears to function as a general longevity factor for various signaling pathways, which is different from the specific function of HEL-1. PMID:27153157

  11. Resveratrol Does Not Affect Health, Longevity in Population Study

    MedlinePlus

    ... You are here Home Resveratrol does not affect health, longevity in population study May 16, 2014 Resveratrol, ... disease. Researchers have found it to improve the health (and in some cases, longevity) of animals, including ...

  12. Plasma long-chain free fatty acids predict mammalian longevity

    PubMed Central

    Jové, Mariona; Naudí, Alba; Aledo, Juan Carlos; Cabré, Rosanna; Ayala, Victoria; Portero-Otin, Manuel; Barja, Gustavo; Pamplona, Reinald

    2013-01-01

    Membrane lipid composition is an important correlate of the rate of aging of animals and, therefore, the determination of their longevity. In the present work, the use of high-throughput technologies allowed us to determine the plasma lipidomic profile of 11 mammalian species ranging in maximum longevity from 3.5 to 120 years. The non-targeted approach revealed a specie-specific lipidomic profile that accurately predicts the animal longevity. The regression analysis between lipid species and longevity demonstrated that the longer the longevity of a species, the lower is its plasma long-chain free fatty acid (LC-FFA) concentrations, peroxidizability index, and lipid peroxidation-derived products content. The inverse association between longevity and LC-FFA persisted after correction for body mass and phylogenetic interdependence. These results indicate that the lipidomic signature is an optimized feature associated with animal longevity, emerging LC-FFA as a potential biomarker of longevity. PMID:24284984

  13. RNA-processing protein TDP-43 regulates FOXO-dependent protein quality control in stress response.

    PubMed

    Zhang, Tao; Baldie, Gerard; Periz, Goran; Wang, Jiou

    2014-10-01

    Protein homeostasis is critical for cell survival and functions during stress and is regulated at both RNA and protein levels. However, how the cell integrates RNA-processing programs with post-translational protein quality control systems is unknown. Transactive response DNA-binding protein (TARDBP/TDP-43) is an RNA-processing protein that is involved in the pathogenesis of major neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here, we report a conserved role for TDP-43, from C. elegans to mammals, in the regulation of protein clearance via activation of FOXO transcription factors. In response to proteotoxic insults, TDP-43 redistributes from the nucleus to the cytoplasm, promoting nuclear translocation of FOXOs and relieving an inhibition of FOXO activity in the nucleus. The interaction between TDP-43 and the FOXO pathway in mammalian cells is mediated by their competitive binding to 14-3-3 proteins. Consistent with FOXO-dependent protein quality control, TDP-43 regulates the levels of misfolded proteins. Therefore, TDP-43 mediates stress responses and couples the regulation of RNA metabolism and protein quality control in a FOXO-dependent manner. The results suggest that compromising the function of TDP-43 in regulating protein homeostasis may contribute to the pathogenesis of related neurodegenerative diseases. PMID:25329970

  14. 17β-estradiol differentially regulates stress circuitry activity in healthy and depressed women.

    PubMed

    Jacobs, Emily G; Holsen, Laura M; Lancaster, Katie; Makris, Nikos; Whitfield-Gabrieli, Sue; Remington, Anne; Weiss, Blair; Buka, Stephen; Klibanski, Anne; Goldstein, Jill M

    2015-02-01

    Many regions within stress neurocircuitry, including the anterior hypothalamus, amygdala, hippocampus, and medial prefrontal cortex, are densely populated with sex steroid receptors. Substantial evidence from animal studies indicates that the gonadal hormone 17β-estradiol (E₂) impacts the structure and function of these regions, but human studies are limited. Characterizing estradiol's role in stress circuitry in vivo in humans may have important clinical implications given the comorbidity between major depressive disorder (MDD), stress circuitry dysfunction and endocrine dysregulation. In this study, we determined estradiol's role in modulating activity within cortical and subcortical stress circuitry regions in healthy and MDD women. Subjects were part of a population-based birth cohort, the New England Family Study. Capitalizing on the endogenous fluctuation in E₂ during the menstrual cycle, we conducted a within-person repeated-measures functional neuroimaging study in which 15 women with recurrent MDD, in remission, and 15 healthy control women underwent hormonal evaluations, behavioral testing, and fMRI scanning on two occasions, under low and high E₂ conditions. Subjects completed an fMRI scan while undergoing a mild visual stress challenge that reliably activated stress neural circuitry. Results demonstrate that E₂ modulates activity across key stress circuitry regions, including bilateral amygdala, hippocampus, and hypothalamus. In healthy women, robust task-evoked BOLD signal changes observed under low E₂ conditions were attenuated under high E₂ conditions. This hormonal capacity to regulate activity in stress circuitry was not observed in MDD women, despite their remitted status, suggesting that dysregulation of gonadal hormone function may be a characteristic trait of the disease. These findings serve to deepen our understanding of estradiol's actions in the healthy brain and the neurobiological mechanisms that may underlie the pronounced

  15. Sprouty2 in the Dorsal Hippocampus Regulates Neurogenesis and Stress Responsiveness in Rats

    PubMed Central

    Dow, Antonia L.; Lin, Tiffany V.; Chartoff, Elena H.; Potter, David; McPhie, Donna L.; Van’t Veer, Ashlee V.; Knoll, Allison T.; Lee, Kristen N.; Neve, Rachael L.; Patel, Tarun B.; Ongur, Dost; Cohen, Bruce M.; Carlezon, William A.

    2015-01-01

    Both the development and relief of stress-related psychiatric conditions such as major depression (MD) and post-traumatic stress disorder (PTSD) have been linked to neuroplastic changes in the brain. One such change involves the birth of new neurons (neurogenesis), which occurs throughout adulthood within discrete areas of the mammalian brain, including the dorsal hippocampus (HIP). Stress can trigger MD and PTSD in humans, and there is considerable evidence that it can decrease HIP neurogenesis in laboratory animals. In contrast, antidepressant treatments increase HIP neurogenesis, and their efficacy is eliminated by ablation of this process. These findings have led to the working hypothesis that HIP neurogenesis serves as a biomarker of neuroplasticity and stress resistance. Here we report that local alterations in the expression of Sprouty2 (SPRY2), an intracellular inhibitor of growth factor function, produces profound effects on both HIP neurogenesis and behaviors that reflect sensitivity to stressors. Viral vector-mediated disruption of endogenous Sprouty2 function (via a dominant negative construct) within the dorsal HIP of adult rats stimulates neurogenesis and produces signs of stress resilience including enhanced extinction of conditioned fear. Conversely, viral vector-mediated elevation of SPRY2 expression intensifies the behavioral consequences of stress. Studies of these manipulations in HIP primary cultures indicate that SPRY2 negatively regulates fibroblast growth factor-2 (FGF2), which has been previously shown to produce antidepressant- and anxiolytic-like effects via actions in the HIP. Our findings strengthen the relationship between HIP plasticity and stress responsiveness, and identify a specific intracellular pathway that could be targeted to study and treat stress-related disorders. PMID:25822989

  16. 17β-Estradiol Differentially Regulates Stress Circuitry Activity in Healthy and Depressed Women

    PubMed Central

    Jacobs, Emily G; Holsen, Laura M; Lancaster, Katie; Makris, Nikos; Whitfield-Gabrieli, Sue; Remington, Anne; Weiss, Blair; Buka, Stephen; Klibanski, Anne; Goldstein, Jill M

    2015-01-01

    Many regions within stress neurocircuitry, including the anterior hypothalamus, amygdala, hippocampus, and medial prefrontal cortex, are densely populated with sex steroid receptors. Substantial evidence from animal studies indicates that the gonadal hormone 17β-estradiol (E2) impacts the structure and function of these regions, but human studies are limited. Characterizing estradiol's role in stress circuitry in vivo in humans may have important clinical implications given the comorbidity between major depressive disorder (MDD), stress circuitry dysfunction and endocrine dysregulation. In this study, we determined estradiol's role in modulating activity within cortical and subcortical stress circuitry regions in healthy and MDD women. Subjects were part of a population-based birth cohort, the New England Family Study. Capitalizing on the endogenous fluctuation in E2 during the menstrual cycle, we conducted a within-person repeated-measures functional neuroimaging study in which 15 women with recurrent MDD, in remission, and 15 healthy control women underwent hormonal evaluations, behavioral testing, and fMRI scanning on two occasions, under low and high E2 conditions. Subjects completed an fMRI scan while undergoing a mild visual stress challenge that reliably activated stress neural circuitry. Results demonstrate that E2 modulates activity across key stress circuitry regions, including bilateral amygdala, hippocampus, and hypothalamus. In healthy women, robust task-evoked BOLD signal changes observed under low E2 conditions were attenuated under high E2 conditions. This hormonal capacity to regulate activity in stress circuitry was not observed in MDD women, despite their remitted status, suggesting that dysregulation of gonadal hormone function may be a characteristic trait of the disease. These findings serve to deepen our understanding of estradiol's actions in the healthy brain and the neurobiological mechanisms that may underlie the pronounced sex

  17. Apolipoprotein D is involved in the mechanisms regulating protection from oxidative stress

    PubMed Central

    Ganfornina, Maria D.; Do Carmo, Sonia; Lora, Jose M.; Torres-Schumann, Sonia; Vogel, Marci; Allhorn, Maria; González, Constancio; Bastiani, Michael J.; Rassart, Eric; Sanchez, Diego

    2008-01-01

    Summary Many nervous system pathologies are associated with increased levels of Apolipoprotein D (ApoD), a lipocalin also expressed during normal development and aging. An ApoD homologous gene in Drosophila, Glial Lazarillo, regulates resistance to stress, and neurodegeneration in the aging brain. Here we study for the first time the protecting potential of ApoD in a vertebrate model organism. Loss of mouse ApoD function increases the sensitivity to oxidative stress and the levels of brain lipid peroxidation, and impairs locomotor and learning abilities. Human ApoD over-expression in the mouse brain produces opposite effects, increasing survival and preventing the raise of brain lipid peroxides after oxidant treatment. These observations, together with its transcriptional up-regulation in the brain upon oxidative insult, identify ApoD as an acute response protein with a protective and therefore beneficial function mediated by the control of peroxidated lipids. PMID:18419796

  18. Multifaceted emotion regulation, stress and affect in mothers of young children.

    PubMed

    Deater-Deckard, Kirby; Li, Mengjiao; Bell, Martha Ann

    2016-01-01

    We tested a novel multi-component emotion self-regulation construct that captured physiological (vagal tone), cognitive (reappraisal) and temperament (effortful control) aspects of emotion regulation (ER) as a moderator of the link between more stressors and greater negative/less positive affectivity (NA and PA). A socio-economically diverse sample of 151 women with young children completed questionnaires and a laboratory visit (including cognitive and parent-child interaction tasks and vagal tone measurement). Women with more stressors had more NA and less PA. Furthermore, for NA only, having more stressors was substantially associated with NA but only among women with the lowest ER. This pattern was evident for the composite as well as individual indicators of ER. Results were not attributable to individual differences in executive function. Findings are discussed in light of the diathesis-stress model of stress and coping. PMID:25759238

  19. Victimization and Biological Stress Responses in Urban Adolescents: Emotion Regulation as a Moderator.

    PubMed

    Kliewer, Wendy

    2016-09-01

    Associations between urban adolescents' victimization experiences and biological stress responses were examined, as well as emotion regulation as a moderator of these associations. Data from a 4-wave longitudinal study with a low-income, community-based sample (n = 242; 91 % African American; 57 % female; M = 11.98, SD = 1.56 years at baseline) revealed that victimization, assessed over 3 study waves, was associated with an attenuated cortisol response to a stress interview at the final study wave, indicating that responses of the Hypothalamus-Pituitary-Adrenal (HPA) axis were dysregulated. Cortisol responses were moderated by caregiver-reported adolescent emotion regulation, suggesting that this modifiable protective factor that is taught in many school-based prevention programs could help reduce harm associated with HPA axis dysregulation linked to victimization. PMID:26676938

  20. HDAC6 regulates GR signaling in serotonin pathways with critical impact on stress resilience

    PubMed Central

    Espallergues, Julie; Teegarden, Sarah L.; Veerakumar, Avin; Boulden, Janette; Challis, Collin; Jochems, Jeanine; Chan, Michael; Petersen, Tess; Deneris, Evan; Matthias, Patrick; Hahn, Chang-Gyu; Lucki, Irwin; Beck, Sheryl G.; Berton, Olivier

    2012-01-01

    Genetic variations in certain components of the glucocorticoid receptor (GR) chaperone complex have been associated with the development of stress-related affective disorders and individual variability in therapeutic responses to antidepressants. Mechanisms that link GR chaperoning and stress susceptibility are not well understood. Here, we show that the effects of glucocorticoid hormones on socioaffective behaviors are critically regulated via reversible acetylation of Hsp90, a key component of the GR chaperone complex. We provide pharmacological and genetic evidence indicating that the cytoplasmic lysine deacetylase HDAC6 controls Hsp90 acetylation in the brain, and thereby modulates Hsp90-GR protein-protein interactions, as well as hormone- and stress-induced GR translocation, with a critical impact on GR downstream signaling and behavior. Pet1-Cre driven deletion of HDAC6 in serotonin neurons, the densest HDAC6-expressing cell group in the mouse brain, dramatically reduced acute anxiogenic effects of the glucocorticoid hormone corticosterone in the open field, elevated plus maze, and social interaction tests. Serotonin-selective depletion of HDAC6 also blocked the expression of social avoidance in mice exposed to chronic social defeat and concurrently prevented the electrophysiological and morphological changes induced, in serotonin neurons, by this murine model of traumatic stress. Together, these results identify HDAC6 inhibition as a potential new strategy for pro-resilience and antidepressant interventions through regulation of the Hsp90-GR heterocomplex and focal prevention of GR signaling in serotonin pathways. Our data thus uncover an alternate mechanism by which pan-HDAC inhibitors may regulate stress-related behaviors independently of their action on histones. PMID:22457490

  1. microRNAs: Emerging Targets Regulating Oxidative Stress in the Models of Parkinson's Disease

    PubMed Central

    Xie, Yangmei; Chen, Yinghui

    2016-01-01

    Parkinson's disease (PD) is the second most common neurodegenerative disorder. This chronic, progressive disease is characterized by loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and the presence of cytoplasmic inclusions called Lewy bodies (LBs) in surviving neurons. PD is attributed to a combination of environment and genetic factors, but the precise underlying molecular mechanisms remain elusive. Oxidative stress is generally recognized as one of the main causes of PD, and excessive reactive oxygen species (ROS) can lead to DA neuron vulnerability and eventual death. Several studies have demonstrated that small non-coding RNAs termed microRNAs (miRNAs) can regulate oxidative stress in vitro and in vivo models of PD. Relevant miRNAs involved in oxidative stress can prevent ROS-mediated damage to DA neurons, suggesting that specific miRNAs may be putative targets for novel therapeutic targets in PD. PMID:27445669

  2. Genome-Wide Survey of Cold Stress Regulated Alternative Splicing in Arabidopsis thaliana with Tiling Microarray

    PubMed Central

    Leviatan, Noam; Alkan, Noam; Leshkowitz, Dena; Fluhr, Robert

    2013-01-01

    Alternative splicing plays a major role in expanding the potential informational content of eukaryotic genomes. It is an important post-transcriptional regulatory mechanism that can increase protein diversity and affect mRNA stability. Alternative splicing is often regulated in a tissue-specific and stress-responsive manner. Cold stress, which adversely affects plant growth and development, regulates the transcription and splicing of plant splicing factors. This can affect the pre-mRNA processing of many genes. To identify cold regulated alternative splicing we applied Affymetrix Arabidopsis tiling arrays to survey the transcriptome under cold treatment conditions. A novel algorithm was used for detection of statistically relevant changes in intron expression within a transcript between control and cold growth conditions. A reverse transcription polymerase chain reaction (RT-PCR) analysis of a number of randomly selected genes confirmed the changes in splicing patterns under cold stress predicted by tiling array. Our analysis revealed new types of cold responsive genes. While their expression level remains relatively unchanged under cold stress their splicing pattern shows detectable changes in the relative abundance of isoforms. The majority of cold regulated alternative splicing introduced a premature termination codon (PTC) into the transcripts creating potential targets for degradation by the nonsense mediated mRNA decay (NMD) process. A number of these genes were analyzed in NMD-defective mutants by RT-PCR and shown to evade NMD. This may result in new and truncated proteins with altered functions or dominant negative effects. The results indicate that cold affects both quantitative and qualitative aspects of gene expression. PMID:23776682

  3. Nitric Oxide Mitigates Salt Stress by Regulating Levels of Osmolytes and Antioxidant Enzymes in Chickpea.

    PubMed

    Ahmad, Parvaiz; Abdel Latef, Arafat A; Hashem, Abeer; Abd Allah, Elsayed F; Gucel, Salih; Tran, Lam-Son P

    2016-01-01

    This work was designed to evaluate whether external application of nitric oxide (NO) in the form of its donor S-nitroso-N-acetylpenicillamine (SNAP) could mitigate the deleterious effects of NaCl stress on chickpea (Cicer arietinum L.) plants. SNAP (50 μM) was applied to chickpea plants grown under non-saline and saline conditions (50 and 100 mM NaCl). Salt stress inhibited growth and biomass yield, leaf relative water content (LRWC) and chlorophyll content of chickpea plants. High salinity increased electrolyte leakage, carotenoid content and the levels of osmolytes (proline, glycine betaine, soluble proteins and soluble sugars), hydrogen peroxide (H2O2) and malondialdehyde (MDA), as well as the activities of antioxidant enzymes, such as superoxide dismutase (SOD), catalase (CAT), ascorbate peroxidase (APX), and glutathione reductase in chickpea plants. Expression of the representative SOD, CAT and APX genes examined was also up-regulated in chickpea plants by salt stress. On the other hand, exogenous application of NO to salinized plants enhanced the growth parameters, LRWC, photosynthetic pigment production and levels of osmolytes, as well as the activities of examined antioxidant enzymes which is correlated with up-regulation of the examined SOD, CAT and APX genes, in comparison with plants treated with NaCl only. Furthermore, electrolyte leakage, H2O2 and MDA contents showed decline in salt-stressed plants supplemented with NO as compared with those in NaCl-treated plants alone. Thus, the exogenous application of NO protected chickpea plants against salt stress-induced oxidative damage by enhancing the biosyntheses of antioxidant enzymes, thereby improving plant growth under saline stress. Taken together, our results demonstrate that NO has capability to mitigate the adverse effects of high salinity on chickpea plants by improving LRWC, photosynthetic pigment biosyntheses, osmolyte accumulation and antioxidative defense system. PMID:27066020

  4. Nitric Oxide Mitigates Salt Stress by Regulating Levels of Osmolytes and Antioxidant Enzymes in Chickpea

    PubMed Central

    Ahmad, Parvaiz; Abdel Latef, Arafat A.; Hashem, Abeer; Abd_Allah, Elsayed F.; Gucel, Salih; Tran, Lam-Son P.

    2016-01-01

    This work was designed to evaluate whether external application of nitric oxide (NO) in the form of its donor S-nitroso-N-acetylpenicillamine (SNAP) could mitigate the deleterious effects of NaCl stress on chickpea (Cicer arietinum L.) plants. SNAP (50 μM) was applied to chickpea plants grown under non-saline and saline conditions (50 and 100 mM NaCl). Salt stress inhibited growth and biomass yield, leaf relative water content (LRWC) and chlorophyll content of chickpea plants. High salinity increased electrolyte leakage, carotenoid content and the levels of osmolytes (proline, glycine betaine, soluble proteins and soluble sugars), hydrogen peroxide (H2O2) and malondialdehyde (MDA), as well as the activities of antioxidant enzymes, such as superoxide dismutase (SOD), catalase (CAT), ascorbate peroxidase (APX), and glutathione reductase in chickpea plants. Expression of the representative SOD, CAT and APX genes examined was also up-regulated in chickpea plants by salt stress. On the other hand, exogenous application of NO to salinized plants enhanced the growth parameters, LRWC, photosynthetic pigment production and levels of osmolytes, as well as the activities of examined antioxidant enzymes which is correlated with up-regulation of the examined SOD, CAT and APX genes, in comparison with plants treated with NaCl only. Furthermore, electrolyte leakage, H2O2 and MDA contents showed decline in salt-stressed plants supplemented with NO as compared with those in NaCl-treated plants alone. Thus, the exogenous application of NO protected chickpea plants against salt stress-induced oxidative damage by enhancing the biosyntheses of antioxidant enzymes, thereby improving plant growth under saline stress. Taken together, our results demonstrate that NO has capability to mitigate the adverse effects of high salinity on chickpea plants by improving LRWC, photosynthetic pigment biosyntheses, osmolyte accumulation and antioxidative defense system. PMID:27066020

  5. Triterpenoid electrophiles (avicins) activate the innate stress response by redox regulation of a gene battery

    PubMed Central

    Haridas, Valsala; Hanausek, Margaret; Nishimura, Goshi; Soehnge, Holly; Gaikwad, Amos; Narog, Maciej; Spears, Erick; Zoltaszek, Robert; Walaszek, Zbigniew; Gutterman, Jordan U.

    2004-01-01

    Avicins are proapoptotic and anti-inflammatory triterpene electrophiles isolated from an Australian desert tree, Acacia victoriae. The presence of two α,β unsaturated carbonyl groups (Michael reaction sites) in the side chain of the avicin molecule prompted us to study its effects on NF-E2–related factor 2 (Nrf2), a redox-regulated transcription factor that controls the expression of a battery of detoxification and antioxidant proteins via its binding to antioxidant response element (ARE). Avicin D–treated Hep G2 cells showed translocation of Nrf2 into the nucleus and a time-dependent increase in ARE activity. These properties were sensitive to DTT, suggesting that avicins affect one or more critical cysteine residues, probably on the Keap1 molecule. Downstream of ARE, an activation of a battery of stress-induced proteins occurred. The implications of these findings were evaluated in vivo in mouse skin exposed to an ancient stressor, UV light. Avicins inhibited epidermal hyperplasia, reduced p53 mutation, enhanced apoptosis, decreased generation of 8-hydroxy-2′-deoxyguanosine, and enhanced expression of NADPH:quinone oxidoreductase 1 and heme oxygenase-1. These data, combined with our earlier published work, demonstrate that avicins represent a new class of plant stress metabolites capable of activating stress adaptation and suppressing proinflammatory components of the innate immune system in human cells by redox regulation. The relevance for treatment of clinical diseases in which stress responses are dysfunctional or deficient is discussed. PMID:14702110

  6. Could FaRP-Like Peptides Participate in Regulation of Hyperosmotic Stress Responses in Plants?

    PubMed Central

    Bouteau, François; Bassaglia, Yann; Monetti, Emanuela; Tran, Daniel; Navet, Sandra; Mancuso, Stefano; El-Maarouf-Bouteau, Hayat; Bonnaud-Ponticelli, Laure

    2014-01-01

    The ability to respond to hyperosmotic stress is one of the numerous conserved cellular processes that most of the organisms have to face during their life. In metazoans, some peptides belonging to the FMRFamide-like peptide (FLP) family were shown to participate in osmoregulation via regulation of ion channels; this is, a well-known response to hyperosmotic stress in plants. Thus, we explored whether FLPs exist and regulate osmotic stress in plants. First, we demonstrated the response of Arabidopsis thaliana cultured cells to a metazoan FLP (FLRF). We found that A. thaliana express genes that display typical FLP repeated sequences, which end in RF and are surrounded by K or R, which is typical of cleavage sites and suggests bioactivity; however, the terminal G, allowing an amidation process in metazoan, seems to be replaced by W. Using synthetic peptides, we showed that amidation appears unnecessary to bioactivity in A. thaliana, and we provide evidence that these putative FLPs could be involved in physiological processes related to hyperosmotic stress responses in plants, urging further studies on this topic. PMID:25177313

  7. Cellular stress induces Bax-regulated nuclear bubble budding and rupture followed by nuclear protein release.

    PubMed

    Lindenboim, Liora; Sasson, Tiki; Worman, Howard J; Borner, Christoph; Stein, Reuven

    2014-01-01

    Cellular stress triggers many pathways including nuclear protein redistribution. We previously discovered that this process is regulated by Bax but the underlying mechanism has not yet been studied. Here we define this mechanism by showing that apoptotic stimuli cause Bax-regulated disturbances in lamin A/C and nuclear envelope (NE)-associated proteins which results in the generation and subsequent rupture of nuclear protein-containing bubbles. The bubbles do not contain DNA and are encapsulated by impaired nuclear pore-depleted NE. Stress-induced generation and rupture of nuclear bubbles ultimately leads to the discharge of nuclear proteins into the cytoplasm. This process precedes morphological changes of apoptosis and occurs independently of caspases. Rescue experiments revealed that this Bax effect is non-canonical, i.e. it requires the BH3 domain and α-helices 5 and 6 but it is not inhibited by Bcl(-)xL. Targeting Bax to the NE by the Klarsicht/ANC-1/Syne-1 homology (KASH) domain effectively triggers the generation and rupture of nuclear bubbles. Overall, our findings provide evidence for a novel stress-response, which is regulated by a non-canonical action of Bax on the NE. PMID:25482068

  8. Contributions of the paraventricular thalamic nucleus in the regulation of stress, motivation, and mood

    PubMed Central

    Hsu, David T.; Kirouac, Gilbert J.; Zubieta, Jon-Kar; Bhatnagar, Seema

    2014-01-01

    The purpose of this review is to describe how the function and connections of the paraventricular thalamic nucleus (Pa) may play a role in the regulation of stress and negative emotional behavior. Located in the dorsal midline thalamus, the Pa is heavily innervated by serotonin, norepinephrine, dopamine (DA), corticotropin-releasing hormone, and orexins (ORX), and is the only thalamic nucleus connected to the group of structures comprising the amygdala, bed nucleus of the stria terminalis (BNST), nucleus accumbens (NAcc), and infralimbic/subgenual anterior cingulate cortex (sgACC). These neurotransmitter systems and structures are involved in regulating motivation and mood, and display abnormal functioning in several psychiatric disorders including anxiety, substance use, and major depressive disorders (MDD). Furthermore, rodent studies show that the Pa is consistently and potently activated following a variety of stressors and has a unique role in regulating responses to chronic stressors. These observations provide a compelling rationale for investigating the Pa in the link between stress and negative emotional behavior, and for including the Pa in the neural pathways of stress-related psychiatric disorders. PMID:24653686

  9. Neurotoxin-induced selective ubiquitination and regulation of MEF2A isoform in neuronal stress response

    PubMed Central

    She, Hua; Yang, Qian; Mao, Zixu

    2014-01-01

    The myocyte enhancer factor 2A-D (MEF2) proteins are members of the MCM1-agamous-deficiens-serum (MADS) response factor family of transcription factors. Various MEF2 isoform proteins are enriched in neurons and exhibit distinct patterns of expression in different regions of the brain. In neurons, MEF2 functions as a converging factor to regulate many neuronal functions including survival. MEF2 activities are tightly controlled in neurons in response to stress. Whether stress signal may differentially regulate MEF2s remains largely unknown. In this work, we showed that MEF2A but not MEF2C or MEF2D was modified by ubiquitination in dopaminergic neuronal cell line SN4741 cells. MEF2A was ubiquitinated at its N’-terminus, and the ubiquitination of MEF2A was first detectable in the nuclear compartment and later in the cytoplasm. Ubiquitination of MEF2A correlated with reduced DNA-binding activity and transcriptional activity. More importantly, disturbing the degradation of ubiquitinated MEF2A through proteasome pathway by neurotoxins known to induce Parkinson’s disease (PD) features in model animals caused accumulation of ubiquitinated MEF2A, reduced MEF2 activity, and impaired cellular viability. Our work thus provides the first evidence to demonstrate an isoforms specific regulation of MEF2s by ubiquitination-proteasome pathway in dopaminergic neuronal cell by neurotoxins, suggesting that stress signal and cellular context dependent dysregulation of MEF2s may underlie the loss of neuronal viability. PMID:22764880

  10. A salt-regulated peptide derived from the CAP superfamily protein negatively regulates salt-stress tolerance in Arabidopsis

    PubMed Central

    Chien, Pei-Shan; Nam, Hong Gil; Chen, Yet-Ran

    2015-01-01

    High salinity has negative impacts on plant growth through altered water uptake and ion-specific toxicities. Plants have therefore evolved an intricate regulatory network in which plant hormones play significant roles in modulating physiological responses to salinity. However, current understanding of the plant peptides involved in this regulatory network remains limited. Here, we identified a salt-regulated peptide in Arabidopsis. The peptide was 11 aa and was derived from the C terminus of a cysteine-rich secretory proteins, antigen 5, and pathogenesis-related 1 proteins (CAP) superfamily. This peptide was found by searching homologues in Arabidopsis using the precursor of a tomato CAP-derived peptide (CAPE) that was initially identified as an immune signal. In searching for a CAPE involved in salt responses, we screened CAPE precursor genes that showed salt-responsive expression and found that the PROAtCAPE1 (AT4G33730) gene was regulated by salinity. We confirmed the endogenous Arabidopsis CAP-derived peptide 1 (AtCAPE1) by mass spectrometry and found that a key amino acid residue in PROAtCAPE1 is critical for AtCAPE1 production. Moreover, although PROAtCAPE1 was expressed mainly in the roots, AtCAPE1 was discovered to be upregulated systemically upon salt treatment. The salt-induced AtCAPE1 negatively regulated salt tolerance by suppressing several salt-tolerance genes functioning in the production of osmolytes, detoxification, stomatal closure control, and cell membrane protection. This discovery demonstrates that AtCAPE1, a homologue of tomato immune regulator CAPE1, plays an important role in the regulation of salt stress responses. Our discovery thus suggests that the peptide may function in a trade-off between pathogen defence and salt tolerance. PMID:26093145

  11. RNA helicase HEL-1 promotes longevity by specifically activating DAF-16/FOXO transcription factor signaling in Caenorhabditis elegans

    PubMed Central

    Seo, Mihwa; Seo, Keunhee; Hwang, Wooseon; Koo, Hee Jung; Hahm, Jeong-Hoon; Yang, Jae-Seong; Han, Seong Kyu; Hwang, Daehee; Kim, Sanguk; Jang, Sung Key; Lee, Yoontae; Nam, Hong Gil; Lee, Seung-Jae V.

    2015-01-01

    The homeostatic maintenance of the genomic DNA is crucial for regulating aging processes. However, the role of RNA homeostasis in aging processes remains unknown. RNA helicases are a large family of enzymes that regulate the biogenesis and homeostasis of RNA. However, the functional significance of RNA helicases in aging has not been explored. Here, we report that a large fraction of RNA helicases regulate the lifespan of Caenorhabditis elegans. In particular, we show that a DEAD-box RNA helicase, helicase 1 (HEL-1), promotes longevity by specifically activating the DAF-16/forkhead box O (FOXO) transcription factor signaling pathway. We find that HEL-1 is required for the longevity conferred by reduced insulin/insulin-like growth factor 1 (IGF-1) signaling (IIS) and is sufficient for extending lifespan. We further show that the expression of HEL-1 in the intestine and neurons contributes to longevity. HEL-1 enhances the induction of a large fraction of DAF-16 target genes. Thus, the RNA helicase HEL-1 appears to promote longevity in response to decreased IIS as a transcription coregulator of DAF-16. Because HEL-1 and IIS are evolutionarily well conserved, a similar mechanism for longevity regulation via an RNA helicase-dependent regulation of FOXO signaling may operate in mammals, including humans. PMID:26195740

  12. RNA helicase HEL-1 promotes longevity by specifically activating DAF-16/FOXO transcription factor signaling in Caenorhabditis elegans.

    PubMed

    Seo, Mihwa; Seo, Keunhee; Hwang, Wooseon; Koo, Hee Jung; Hahm, Jeong-Hoon; Yang, Jae-Seong; Han, Seong Kyu; Hwang, Daehee; Kim, Sanguk; Jang, Sung Key; Lee, Yoontae; Nam, Hong Gil; Lee, Seung-Jae V

    2015-08-01

    The homeostatic maintenance of the genomic DNA is crucial for regulating aging processes. However, the role of RNA homeostasis in aging processes remains unknown. RNA helicases are a large family of enzymes that regulate the biogenesis and homeostasis of RNA. However, the functional significance of RNA helicases in aging has not been explored. Here, we report that a large fraction of RNA helicases regulate the lifespan of Caenorhabditis elegans. In particular, we show that a DEAD-box RNA helicase, helicase 1 (HEL-1), promotes longevity by specifically activating the DAF-16/forkhead box O (FOXO) transcription factor signaling pathway. We find that HEL-1 is required for the longevity conferred by reduced insulin/insulin-like growth factor 1 (IGF-1) signaling (IIS) and is sufficient for extending lifespan. We further show that the expression of HEL-1 in the intestine and neurons contributes to longevity. HEL-1 enhances the induction of a large fraction of DAF-16 target genes. Thus, the RNA helicase HEL-1 appears to promote longevity in response to decreased IIS as a transcription coregulator of DAF-16. Because HEL-1 and IIS are evolutionarily well conserved, a similar mechanism for longevity regulation via an RNA helicase-dependent regulation of FOXO signaling may operate in mammals, including humans. PMID:26195740

  13. TROPICAL SPIDERWORT SEEDBANK DYNAMICS AND LONGEVITY

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Tropical species are often expected to have short seedbank longevity and fairly predictable seedbank dynamics. This is not the case for tropical spiderwort (also known as Benghal dayflower, Commelina benghalensis L.). Although seedbanks near the surface appear to germinate rapidly – successively dep...

  14. Longevity and Mortality in Down's Syndrome.

    ERIC Educational Resources Information Center

    Thase, M. E.

    1982-01-01

    Research on the longevity of Down's Syndrome persons is reviewed, and the life span is noted to have increased, although the overall mortality rate is still five times greater than that for the general population. Statistics on causes of mortality (such as immunological abnormalities, congenital heart disease, and malignancy) are summarized. (CL)

  15. Translational genomics for improving sow reproductive longevity

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Sow reproductive longevity is a composite trait that is expressed throughout life that depends on the potential of females to resume ovarian cyclicity, re-breed, and farrow multiple parities. Approximately 50% of sows are culled annually with more than one third due to poor fertility. Age at puberty...

  16. Longevity and Education: Survey Results, 2002.

    ERIC Educational Resources Information Center

    Silverman, Barbara; Lange, Mary Sue

    In order to better serve the needs of people in midlife and beyond, Mt. San Antonio College (Mt. SAC), California, is considering the establishment of a Center for Longevity and Education (CLE). The CLE mission would be to foster a supportive environment for lifelong learning and life transitions for midlife and beyond, while channeling the…

  17. Nectarine promotes longevity in Drosophila melanogaster

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Aging is associated with increased oxidative damage and gradual decline of physiology function with age, and is modulated by numerous genetic and environmental factors. Functional fruits are thought to be ideal candidates for promoting longevity and healthspan due to their high contents of polypheno...

  18. Longevity and Depreciation of Audiovisual Equipment.

    ERIC Educational Resources Information Center

    Post, Richard

    1987-01-01

    Describes results of survey of media service directors at public universities in Ohio to determine the expected longevity of audiovisual equipment. Use of the Delphi technique for estimates is explained, results are compared with an earlier survey done in 1977, and use of spreadsheet software to calculate depreciation is discussed. (LRW)

  19. BLIMP-1/BLMP-1 and Metastasis-Associated Protein Regulate Stress Resistant Development in Caenorhabditis elegans.

    PubMed

    Hyun, Moonjung; Kim, Jeongho; Dumur, Catherine; Schroeder, Frank C; You, Young-Jai

    2016-08-01

    Environmental stress triggers multilevel adaptations in animal development that depend in part on epigenetic mechanisms. In response to harsh environmental conditions and pheromone signals, Caenorhabditis elegans larvae become the highly stress-resistant and long-lived dauer. Despite extensive studies of dauer formation pathways that integrate specific environmental cues and appear to depend on transcriptional reprogramming, the role of epigenetic regulation in dauer development has remained unclear. Here we report that BLMP-1, the BLIMP-1 ortholog, regulates dauer formation via epigenetic pathways; in the absence of TGF-β signaling (in daf-7 mutants), lack of blmp-1 caused lethality. Using this phenotype, we screened 283 epigenetic factors, and identified lin-40, a homolog of metastasis-associate protein 1 (MTA1) as an interactor of BLMP-1 The interaction between LIN-40 and BLMP-1 is conserved because mammalian homologs for both MTA1 and BLIMP-1 could also interact. From microarray studies, we identified several downstream target genes of blmp-1: npr-3, nhr-23, ptr-4, and sams-1 Among them S-adenosyl methionine synthase (SAMS-1), is the key enzyme for production of SAM used in histone methylation. Indeed, blmp-1 is necessary for controlling histone methylation level in daf-7 mutants, suggesting BLMP-1 regulates the expression of SAMS-1, which in turn may regulate histone methylation and dauer formation. Our results reveal a new interaction between BLMP-1/BLIMP-1 and LIN-40/MTA1, as well as potential epigenetic downstream pathways, whereby these proteins cooperate to regulate stress-specific developmental adaptations. PMID:27334271

  20. Different cucumber CsYUC genes regulate response to abiotic stresses and flower development.

    PubMed

    Yan, Shuangshuang; Che, Gen; Ding, Lian; Chen, Zijing; Liu, Xiaofeng; Wang, Hongyin; Zhao, Wensheng; Ning, Kang; Zhao, Jianyu; Tesfamichael, Kiflom; Wang, Qian; Zhang, Xiaolan

    2016-01-01

    The phytohormone auxin is essential for plant growth and development, and YUCCA (YUC) proteins catalyze a rate-limiting step for endogenous auxin biosynthesis. Despite YUC family genes have been isolated from several species, systematic expression analyses of YUCs in response to abiotic stress are lacking, and little is known about the function of YUC homologs in agricultural crops. Cucumber (Cucumis sativus L.) is a world cultivated vegetable crop with great economical and nutritional value. In this study, we isolated 10 YUC family genes (CsYUCs) from cucumber and explored their expression pattern under four types of stress treatments. Our data showed that CsYUC8 and CsYUC9 were specifically upregulated to elevate the auxin level under high temperature. CsYUC10b was dramatically increased but CsYUC4 was repressed in response to low temperature. CsYUC10a and CsYUC11 act against the upregulation of CsYUC10b under salinity stress, suggesting that distinct YUC members participate in different stress response, and may even antagonize each other to maintain the proper auxin levels in cucumber. Further, CsYUC11 was specifically expressed in the male flower in cucumber, and enhanced tolerance to salinity stress and regulated pedicel and stamen development through auxin biosynthesis in Arabidopsis. PMID:26857463

  1. Conserved cellular function and stress-mediated regulation among members of the proteolipid protein family.

    PubMed

    Fernández, María E; Alfonso, Julieta; Brocco, Marcela A; Frasch, Alberto C

    2010-05-01

    Chronic stress causes morphological alterations in the hippocampus of rodents and tree shrews, including atrophy of CA3 dendrites and loss of synapses. The molecular mechanisms underlying these structural changes remain largely unknown. We have previously identified M6a as a stress responsive gene and shown that M6a is involved in filopodium/spine outgrowth and, likely, synapse formation. M6a belongs to the proteolipid protein (PLP) family, all of their members having four transmembrane domains that allow their localization at the plasma membrane. In the present work, we analyzed other members of this family, the closely related M6b as well as PLP and its splice variant DM20. We found that chronic restraint stress in mice reduces M6b and DM20, but not PLP, mRNA levels in the hippocampus. In addition, M6b and DM20, but again not PLP, induce filopodium formation in primary cultures of hippocampal neurons. Several M6b protein isoforms were studied, all of them having similar effects except for the one lacking the transmembrane domains. Our results reveal a conserved cellular function and a stress-mediated regulation among members of the proteolipid protein family, suggesting an involvement of proteolipid proteins in the stress response. PMID:19937804

  2. Different cucumber CsYUC genes regulate response to abiotic stresses and flower development

    PubMed Central

    Yan, Shuangshuang; Che, Gen; Ding, Lian; Chen, Zijing; Liu, Xiaofeng; Wang, Hongyin; Zhao, Wensheng; Ning, Kang; Zhao, Jianyu; Tesfamichael, Kiflom; Wang, Qian; Zhang, Xiaolan

    2016-01-01

    The phytohormone auxin is essential for plant growth and development, and YUCCA (YUC) proteins catalyze a rate-limiting step for endogenous auxin biosynthesis. Despite YUC family genes have been isolated from several species, systematic expression analyses of YUCs in response to abiotic stress are lacking, and little is known about the function of YUC homologs in agricultural crops. Cucumber (Cucumis sativus L.) is a world cultivated vegetable crop with great economical and nutritional value. In this study, we isolated 10 YUC family genes (CsYUCs) from cucumber and explored their expression pattern under four types of stress treatments. Our data showed that CsYUC8 and CsYUC9 were specifically upregulated to elevate the auxin level under high temperature. CsYUC10b was dramatically increased but CsYUC4 was repressed in response to low temperature. CsYUC10a and CsYUC11 act against the upregulation of CsYUC10b under salinity stress, suggesting that distinct YUC members participate in different stress response, and may even antagonize each other to maintain the proper auxin levels in cucumber. Further, CsYUC11 was specifically expressed in the male flower in cucumber, and enhanced tolerance to salinity stress and regulated pedicel and stamen development through auxin biosynthesis in Arabidopsis. PMID:26857463

  3. Mechanism of H₂O₂-induced oxidative stress regulating viability and biocontrol ability of Rhodotorula glutinis.

    PubMed

    Chen, Jian; Li, Boqiang; Qin, Guozheng; Tian, Shiping

    2015-01-16

    The use of antagonistic yeasts to control postharvest pathogens is a promising alternative to fungicides. The effectiveness of the antagonists against fungal pathogens is greatly dependent on their viability, which is usually mediated by reactive oxygen species (ROS). Here, we investigated the effects of H₂O₂-induced oxidative stress on the viability and biocontrol efficacy of Rhodotorula glutinis and, using flow cytometric analysis, observed the changes of ROS accumulation and apoptosis in the yeast cells with or without H₂O₂ treatment. We found that the viability of R. glutinis decreased in a time- and dose-dependent manner under H₂O₂-induced oxidative stress. Compared to the control, yeast cells exposed to oxidative stress exhibited more accumulation of ROS and higher levels of protein oxidative damage, but showed lower efficacy for biocontrol of Penicillium expansum causing blue mold rot on peach fruit. The results indicate that apoptosis is a main cause of the cell viability loss in R. glutinis, which is attributed to ROS accumulation under oxidative stress. These findings offer a plausible explanation that oxidative stress affects biocontrol efficacy of R. glutinis via regulating its viability and cell apoptosis. PMID:25462935

  4. Sex differences in the locus coeruleus-norepinephrine system and its regulation by stress.

    PubMed

    Bangasser, Debra A; Wiersielis, Kimberly R; Khantsis, Sabina

    2016-06-15

    Women are more likely than men to suffer from post-traumatic stress disorder (PTSD) and major depression. In addition to their sex bias, these disorders share stress as an etiological factor and hyperarousal as a symptom. Thus, sex differences in brain arousal systems and their regulation by stress could help explain increased vulnerability to these disorders in women. Here we review preclinical studies that have identified sex differences in the locus coeruleus (LC)-norepinephrine (NE) arousal system. First, we detail how structural sex differences in the LC can bias females towards increased arousal in response to emotional events. Second, we highlight studies demonstrating that estrogen can increase NE in LC target regions by enhancing the capacity for NE synthesis, while reducing NE degradation, potentially increasing arousal in females. Third, we review data revealing how sex differences in the stress receptor, corticotropin releasing factor 1 (CRF1), can increase LC neuronal sensitivity to CRF in females compared to males. This effect could translate into hyperarousal in women under conditions of CRF hypersecretion that occur in PTSD and depression. The implications of these sex differences for the treatment of stress-related psychiatric disorders are discussed. Moreover, the value of using information regarding biological sex differences to aid in the development of novel pharmacotherapies to better treat men and women with PTSD and depression is also highlighted. This article is part of a Special Issue entitled SI: Noradrenergic System. PMID:26607253

  5. Increased ROS Production: A Component of the Longevity Equation in the Male Mygalomorph, Brachypelma albopilosa

    PubMed Central

    Criscuolo, Francois; Font-Sala, Candide; Bouillaud, Frederic; Poulin, Nicolas; Trabalon, Marie

    2010-01-01

    Background The diversity of longevities encountered in wildlife is one of the most intriguing problems in biology. Evolutionary biologists have proposed different theories to explain how longevity variability may be driven by bad genes expression in late life or by gene pleiotropic effects. This reflexion has stimulated, in the last ten years, an active research on the proximal mechanisms that can shape lifespan. Reactive oxygen species (ROS), i.e., the by-products of oxidative metabolism, have emerged as the main proximate cause of ageing. Because ROS are mainly produced by the mitochondria, their production is linked to metabolic rate, and this may explain the differences in longevity between large and small species. However, their implication in the sex difference in longevity within a species has never been tested, despite the fact that these differences are widespread in the animal kingdom. Methodology/Principal Findings Mitochondrial superoxide production of hemolymph immune cells and antioxidant and oxidative damages plasma levels were measured in adult male and female B. albopilosa at different ages. We found that female spiders are producing less mitochondrial superoxide, are better protected against oxidative attack and are then suffering less oxidative damages than males at adulthood. Conclusions/Significance In tarantulas, once reaching sexual maturity, males have a life expectancy reduced to 1 to 2 years, while females can still live for 20 years, in spite of the fact that females continue to grow and moult. This study evidences an increased exposure of males to oxidative stress due to an increase in mitochondrial superoxide production and a decrease in hemolymph antioxidant defences. Such a phenomenon is likely to be part of the explanation for the sharp reduction of longevity accompanying male tarantula maturity. This opens several fundamental research roads in the future to better understand how reproduction and longevity are linked in an original

  6. ATM regulation of IL-8 links oxidative stress to cancer cell migration and invasion

    PubMed Central

    Chen, Wei-Ta; Ebelt, Nancy D; Stracker, Travis H; Xhemalce, Blerta; Van Den Berg, Carla L; Miller, Kyle M

    2015-01-01

    Ataxia-telangiectasia mutated (ATM) protein kinase regulates the DNA damage response (DDR) and is associated with cancer suppression. Here we report a cancer-promoting role for ATM. ATM depletion in metastatic cancer cells reduced cell migration and invasion. Transcription analyses identified a gene network, including the chemokine IL-8, regulated by ATM. IL-8 expression required ATM and was regulated by oxidative stress. IL-8 was validated as an ATM target by its ability to rescue cell migration and invasion defects in ATM-depleted cells. Finally, ATM-depletion in human breast cancer cells reduced lung tumors in a mouse xenograft model and clinical data validated IL-8 in lung metastasis. These findings provide insights into how ATM activation by oxidative stress regulates IL-8 to sustain cell migration and invasion in cancer cells to promote metastatic potential. Thus, in addition to well-established roles in tumor suppression, these findings identify a role for ATM in tumor progression. DOI: http://dx.doi.org/10.7554/eLife.07270.001 PMID:26030852

  7. Effects of mindfulness-based stress reduction (MBSR) on emotion regulation in social anxiety disorder.

    PubMed

    Goldin, Philippe R; Gross, James J

    2010-02-01

    Mindfulness-based stress reduction (MBSR) is an established program shown to reduce symptoms of stress, anxiety, and depression. MBSR is believed to alter emotional responding by modifying cognitive-affective processes. Given that social anxiety disorder (SAD) is characterized by emotional and attentional biases as well as distorted negative self-beliefs, we examined MBSR-related changes in the brain-behavior indices of emotional reactivity and regulation of negative self-beliefs in patients with SAD. Sixteen patients underwent functional MRI while reacting to negative self-beliefs and while regulating negative emotions using 2 types of attention deployment emotion regulation-breath-focused attention and distraction-focused attention. Post-MBSR, 14 patients completed neuroimaging assessments. Compared with baseline, MBSR completers showed improvement in anxiety and depression symptoms and self-esteem. During the breath-focused attention task (but not the distraction-focused attention task), they also showed (a) decreased negative emotion experience, (b) reduced amygdala activity, and (c) increased activity in brain regions implicated in attentional deployment. MBSR training in patients with SAD may reduce emotional reactivity while enhancing emotion regulation. These changes might facilitate reduction in SAD-related avoidance behaviors, clinical symptoms, and automatic emotional reactivity to negative self-beliefs in adults with SAD. PMID:20141305

  8. PPARs in Regulation of Paraoxonases: Control of Oxidative Stress and Inflammation Pathways

    PubMed Central

    Camps, Jordi; García-Heredia, Anabel; Rull, Anna; Alonso-Villaverde, Carlos; Aragonès, Gerard; Beltrán-Debón, Raúl; Rodríguez-Gallego, Esther; Joven, Jorge

    2012-01-01

    The paraoxonase (PON) group of enzymes, composed of PON1, PON2, and PON3, play an important role in decreasing oxidative stress by degrading lipid peroxides. PON1 synthesis is upregulated by PPAR. Several pharmacological compounds (acting as antioxidants and, hence, atheroprotective) stimulate both PPAR activity and PON1 expression. Recent evidence suggests that PON1 and the monocyte chemoattractant protein-1 (MCP-1) are involved in coordinating the inflammatory response in damaged tissues; PPAR may be central in the regulation of these biochemical pathways. This article reviews the state of knowledge on PON1 biochemistry and function, the influence of genetic variation, and the regulation of PON1 expression by pharmaceutical compounds that increase PPAR activity. We also describe recent lines of evidence suggesting links between PON1 and MCP-1 and how their production may be regulated by PPAR. PMID:22315585

  9. Regulation of mitochondrial oxidative stress by β-arrestins in cultured human cardiac fibroblasts

    PubMed Central

    Philip, Jennifer L.; Razzaque, Md. Abdur; Han, Mei; Li, Jinju; Theccanat, Tiju; Xu, Xianyao; Akhter, Shahab A.

    2015-01-01

    ABSTRACT Oxidative stress in cardiac fibroblasts (CFs) promotes transformation to myofibroblasts and collagen synthesis leading to myocardial fibrosis, a precursor to heart failure (HF). NADPH oxidase 4 (Nox4) is a major source of cardiac reactive oxygen species (ROS); however, mechanisms of Nox4 regulation are unclear. β-arrestins are scaffold proteins that signal in G-protein-dependent and -independent pathways; for example, in ERK activation. We hypothesize that β-arrestins regulate oxidative stress in a Nox4-dependent manner and increase fibrosis in HF. CFs were isolated from normal and failing adult human left ventricles. Mitochondrial ROS/superoxide production was quantitated using MitoSox. β-arrestin and Nox4 expressions were manipulated using adenoviral overexpression or short interfering RNA (siRNA)-mediated knockdown. Mitochondrial oxidative stress and Nox4 expression in CFs were significantly increased in HF. Nox4 knockdown resulted in inhibition of mitochondrial superoxide production and decreased basal and TGF-β-stimulated collagen and α-SMA expression. CF β-arrestin expression was upregulated fourfold in HF. β-arrestin knockdown in failing CFs decreased ROS and Nox4 expression by 50%. β-arrestin overexpression in normal CFs increased mitochondrial superoxide production twofold. These effects were prevented by inhibition of either Nox or ERK. Upregulation of Nox4 seemed to be a primary mechanism for increased ROS production in failing CFs, which stimulates collagen deposition. β-arrestin expression was upregulated in HF and plays an important and newly identified role in regulating mitochondrial superoxide production via Nox4. The mechanism for this effect seems to be ERK-mediated. Targeted inhibition of β-arrestins in CFs might decrease oxidative stress as well as pathological cardiac fibrosis. PMID:26449263

  10. Vasomotor Regulation of Coronary Microcirculation by Oxidative Stress: Role of Arginase

    PubMed Central

    Kuo, Lih; Hein, Travis W.

    2013-01-01

    Overproduction of reactive oxygen species, i.e., oxidative stress, is associated with the activation of redox signaling pathways linking to inflammatory insults and cardiovascular diseases by impairing endothelial function and consequently blood flow dysregulation due to microvascular dysfunction. This review focuses on the regulation of vasomotor function in the coronary microcirculation by endothelial nitric oxide (NO) during oxidative stress and inflammation related to the activation of L-arginine consuming enzyme arginase. Superoxide produced in the vascular wall compromises vasomotor function by not only scavenging endothelium-derived NO but also inhibiting prostacyclin synthesis due to formation of peroxynitrite. The upregulation of arginase contributes to the deficiency of endothelial NO and microvascular dysfunction in various vascular diseases by initiating or following oxidative stress and inflammation. Hydrogen peroxide, a diffusible and stable oxidizing agent, exerts vasodilator function and plays important roles in the physiological regulation of coronary blood flow. In occlusive coronary ischemia, the release of hydrogen peroxide from the microvasculature helps to restore vasomotor function of coronary collateral microvessels with exercise training. However, excessive production and prolonged exposure of microvessels to hydrogen peroxide impairs NO-mediated endothelial function by reducing L-arginine availability through hydroxyl radical-dependent upregulation of arginase. The redox signaling can be a double-edged sword in the microcirculation, which helps tissue survival in one way by improving vasomotor regulation and elicits oxidative stress and tissue injury in the other way by causing vascular dysfunction. The impact of vascular arginase on the development of vasomotor dysfunction associated with angiotensin II receptor activation, hypertension, ischemia-reperfusion, hypercholesterolemia, and inflammatory insults is discussed. PMID:23966996

  11. IκB Kinase Regulates Social Defeat Stress-Induced Synaptic and Behavioral Plasticity

    PubMed Central

    Christoffel, Daniel J.; Golden, Sam A.; Dumitriu, Dani; Robison, Alfred J.; Janssen, William G.; Ahn, H. Francisca; Krishnan, Vaishnav; Reyes, Cindy M.; Han, Ming-Hu; Ables, Jessica L.; Eisch, Amelia J.; Dietz, David M.; Ferguson, Deveroux; Neve, Rachael L.; Greengard, Paul; Kim, Yong; Morrison, John H.; Russo, Scott J.

    2011-01-01

    The neurobiological underpinnings of mood and anxiety disorders have been linked to the nucleus accumbens (NAc), a region important in processing the rewarding and emotional salience of stimuli. Using chronic social defeat stress, an animal model of mood and anxiety disorders, we investigated whether alterations in synaptic plasticity are responsible for the long-lasting behavioral symptoms induced by this form of stress. We hypothesized that chronic social defeat stress alters synaptic strength or connectivity of medium spiny neurons (MSNs) in the NAc to induce social avoidance. To test this, we analyzed the synaptic profile of MSNs via confocal imaging of Lucifer-yellow-filled cells, ultrastructural analysis of the postsynaptic density, and electrophysiological recordings of miniature EPSCs (mEPSCs) in mice after social defeat. We found that NAc MSNs have more stubby spine structures with smaller postsynaptic densities and an increase in the frequency of mEPSCs after social defeat. In parallel to these structural changes, we observed significant increases in IκB kinase (IKK) in the NAc after social defeat, a molecular pathway that has been shown to regulate neuronal morphology. Indeed, we find using viral-mediated gene transfer of dominant-negative and constitutively active IKK mutants that activation of IKK signaling pathways during social defeat is both necessary and sufficient to induce synaptic alterations and behavioral effects of the stress. These studies establish a causal role for IKK in regulating stress-induced adaptive plasticity and may present a novel target for drug development in the treatment of mood and anxiety disorders in humans. PMID:21209217

  12. Systematic dissection of roles for chromatin regulators in a yeast stress response.

    PubMed

    Weiner, Assaf; Chen, Hsiuyi V; Liu, Chih Long; Rahat, Ayelet; Klien, Avital; Soares, Luis; Gudipati, Mohanram; Pfeffner, Jenna; Regev, Aviv; Buratowski, Stephen; Pleiss, Jeffrey A; Friedman, Nir; Rando, Oliver J

    2012-01-01

    Packaging of eukaryotic genomes into chromatin has wide-ranging effects on gene transcription. Curiously, it is commonly observed that deletion of a global chromatin regulator affects expression of only a limited subset of genes bound to or modified by the regulator in question. However, in many single-gene studies it has become clear that chromatin regulators often do not affect steady-state transcription, but instead are required for normal transcriptional reprogramming by environmental cues. We therefore have systematically investigated the effects of 83 histone mutants, and 119 gene deletion mutants, on induction/repression dynamics of 170 transcripts in response to diamide stress in yeast. Importantly, we find that chromatin regulators play far more pronounced roles during gene induction/repression than they do in steady-state expression. Furthermore, by jointly analyzing the substrates (histone mutants) and enzymes (chromatin modifier deletions) we identify specific interactions between histone modifications and their regulators. Combining these functional results with genome-wide mapping of several histone marks in the same time course, we systematically investigated the correspondence between histone modification occurrence and function. We followed up on one pathway, finding that Set1-dependent H3K4 methylation primarily acts as a gene repressor during multiple stresses, specifically at genes involved in ribosome biosynthesis. Set1-dependent repression of ribosomal genes occurs via distinct pathways for ribosomal protein genes and ribosomal biogenesis genes, which can be separated based on genetic requirements for repression and based on chromatin changes during gene repression. Together, our dynamic studies provide a rich resource for investigating chromatin regulation, and identify a significant role for the "activating" mark H3K4me3 in gene repression. PMID:22912562

  13. Systematic Dissection of Roles for Chromatin Regulators in a Yeast Stress Response

    PubMed Central

    Liu, Chih Long; Rahat, Ayelet; Klien, Avital; Soares, Luis; Gudipati, Mohanram; Pfeffner, Jenna; Regev, Aviv; Buratowski, Stephen; Pleiss, Jeffrey A.; Friedman, Nir; Rando, Oliver J.

    2012-01-01

    Packaging of eukaryotic genomes into chromatin has wide-ranging effects on gene transcription. Curiously, it is commonly observed that deletion of a global chromatin regulator affects expression of only a limited subset of genes bound to or modified by the regulator in question. However, in many single-gene studies it has become clear that chromatin regulators often do not affect steady-state transcription, but instead are required for normal transcriptional reprogramming by environmental cues. We therefore have systematically investigated the effects of 83 histone mutants, and 119 gene deletion mutants, on induction/repression dynamics of 170 transcripts in response to diamide stress in yeast. Importantly, we find that chromatin regulators play far more pronounced roles during gene induction/repression than they do in steady-state expression. Furthermore, by jointly analyzing the substrates (histone mutants) and enzymes (chromatin modifier deletions) we identify specific interactions between histone modifications and their regulators. Combining these functional results with genome-wide mapping of several histone marks in the same time course, we systematically investigated the correspondence between histone modification occurrence and function. We followed up on one pathway, finding that Set1-dependent H3K4 methylation primarily acts as a gene repressor during multiple stresses, specifically at genes involved in ribosome biosynthesis. Set1-dependent repression of ribosomal genes occurs via distinct pathways for ribosomal protein genes and ribosomal biogenesis genes, which can be separated based on genetic requirements for repression and based on chromatin changes during gene repression. Together, our dynamic studies provide a rich resource for investigating chromatin regulation, and identify a significant role for the “activating” mark H3K4me3 in gene repression. PMID:22912562

  14. A Universally Conserved ATPase Regulates the Oxidative Stress Response in Escherichia coli*

    PubMed Central

    Wenk, Meike; Ba, Qiaorui; Erichsen, Veronika; MacInnes, Katherine; Wiese, Heike; Warscheid, Bettina; Koch, Hans-Georg

    2012-01-01

    YchF is an evolutionarily conserved ATPase of unknown function. In humans, the YchF homologue hOla1 appears to influence cell proliferation and was found to be up-regulated in many tumors. A possible involvement in regulating the oxidative stress response was also suggested, but details on the underlying mechanism are lacking. For gaining insight into YchF function, we used Escherichia coli as a model organism and found that YchF overexpression resulted in H2O2 hypersensitivity. This was not caused by transcriptional or translational down-regulation of H2O2-scavenging enzymes. Instead, we observed YchF-dependent inhibition of catalase activity and a direct interaction with the major E. coli catalase KatG. KatG inhibition was dependent on the ATPase activity of YchF and was regulated by post-translational modifications, most likely including an H2O2-dependent dephosphorylation. We furthermore showed that YchF expression is repressed by the transcription factor OxyR and further post-translationally modified in response to H2O2. In summary, our data show that YchF functions as a novel negative regulator of the oxidative stress response in E. coli. Considering the available data on hOla1, YchF/Ola1 most likely execute similar functions in bacteria and humans, and their up-regulation inhibits the ability of the cells to scavenge damaging reactive oxygen species. PMID:23139412

  15. Nrf2, a Guardian of Healthspan and Gatekeeper of Species Longevity

    PubMed Central

    Lewis, Kaitlyn N.; Mele, James; Hayes, John D.; Buffenstein, Rochelle

    2010-01-01

    Although aging is a ubiquitous process that prevails in all organisms, the mechanisms governing both the rate of decline in functionality and the age of onset remain elusive. A profound constitutively upregulated cytoprotective response is commonly observed in naturally long-lived species and experimental models of extensions to lifespan (e.g., genetically-altered and/or experimentally manipulated organisms), as indicated by enhanced resistance to stress and upregulated downstream components of the cytoprotective nuclear factor erythroid 2-related factor 2 (Nrf2)-signaling pathway. The transcription factor Nrf2 is constitutively expressed in all tissues, although levels may vary among organs, with the key detoxification organs (kidney and liver) exhibiting highest levels. Nrf2 may be further induced by cellular stressors including endogenous reactive-oxygen species or exogenous electrophiles. The Nrf2-signaling pathway mediates multiple avenues of cytoprotection by activating the transcription of more than 200 genes that are crucial in the metabolism of drugs and toxins, protection against oxidative stress and inflammation, as well as playing an integral role in stability of proteins and in the removal of damaged proteins via proteasomal degradation or autophagy. Nrf2 interacts with other important cell regulators such as tumor suppressor protein 53 (p53) and nuclear factor-kappa beta (NF-κB) and through their combined interactions is the guardian of healthspan, protecting against many age-related diseases including cancer and neurodegeneration. We hypothesize that this signaling pathway plays a critical role in the determination of species longevity and that this pathway may indeed be the master regulator of the aging process. PMID:21031035

  16. Arabidopsis INCURVATA2 Regulates Salicylic Acid and Abscisic Acid Signaling, and Oxidative Stress Responses.

    PubMed

    Micol-Ponce, Rosa; Sánchez-García, Ana Belén; Xu, Qian; Barrero, José María; Micol, José Luis; Ponce, María Rosa

    2015-11-01

    Epigenetic regulatory states can persist through mitosis and meiosis, but the connection between chromatin structure and DNA replication remains unclear. Arabidopsis INCURVATA2 (ICU2) encodes the catalytic subunit of DNA polymerase α, and null alleles of ICU2 have an embryo-lethal phenotype. Analysis of icu2-1, a hypomorphic allele of ICU2, demonstrated that ICU2 functions in chromatin-mediated cellular memory; icu2-1 strongly impairs ICU2 function in the maintenance of repressive epigenetic marks but does not seem to affect ICU2 polymerase activity. To better understand the global function of ICU2 in epigenetic regulation, here we performed a microarray analysis of icu2-1 mutant plants. We found that the genes up-regulated in the icu2-1 mutant included genes encoding transcription factors and targets of the Polycomb Repressive Complexes. The down-regulated genes included many known players in salicylic acid (SA) biosynthesis and accumulation, ABA signaling and ABA-mediated responses. In addition, we found that icu2-1 plants had reduced SA levels in normal conditions; infection by Fusarium oxysporum induced SA accumulation in the En-2 wild type but not in the icu2-1 mutant. The icu2-1 plants were also hypersensitive to salt stress and exogenous ABA in seedling establishment, post-germination growth and stomatal closure, and accumulated more ABA than the wild type in response to salt stress. The icu2-1 mutant also showed high tolerance to the oxidative stress produced by 3-amino-1,2,4-triazole (3-AT). Our results uncover a role for ICU2 in the regulation of genes involved in ABA signaling as well as in SA biosynthesis and accumulation. PMID:26423959

  17. Transcription Factor ADS-4 Regulates Adaptive Responses and Resistance to Antifungal Azole Stress

    PubMed Central

    Wang, Kangji; Zhang, Zhenying; Chen, Xi; Sun, Xianyun; Jin, Cheng

    2015-01-01

    Azoles are commonly used as antifungal drugs or pesticides to control fungal infections in medicine and agriculture. Fungi adapt to azole stress by rapidly activating the transcription of a number of genes, and transcriptional increases in some azole-responsive genes can elevate azole resistance. The regulatory mechanisms that control transcriptional responses to azole stress in filamentous fungi are not well understood. This study identified a bZIP transcription factor, ADS-4 (antifungal drug sensitive-4), as a new regulator of adaptive responses and resistance to antifungal azoles. Transcription of ads-4 in Neurospora crassa cells increased when they were subjected to ketoconazole treatment, whereas the deletion of ads-4 resulted in hypersensitivity to ketoconazole and fluconazole. In contrast, the overexpression of ads-4 increased resistance to fluconazole and ketoconazole in N. crassa. Transcriptome sequencing (RNA-seq) analysis, followed by quantitative reverse transcription (qRT)-PCR confirmation, showed that ADS-4 positively regulated the transcriptional responses of at least six genes to ketoconazole stress in N. crassa. The gene products of four ADS-4-regulated genes are known contributors to azole resistance, including the major efflux pump CDR4 (Pdr5p ortholog), an ABC multidrug transporter (NcAbcB), sterol C-22 desaturase (ERG5), and a lipid transporter (NcRTA2) that is involved in calcineurin-mediated azole resistance. Deletion of the ads-4-homologous gene Afads-4 in Aspergillus fumigatus caused hypersensitivity to itraconazole and ketoconazole, which suggested that ADS-4 is a functionally conserved regulator of adaptive responses to azoles. This study provides important information on a new azole resistance factor that could be targeted by a new range of antifungal pesticides and drugs. PMID:26100701

  18. Bax inhibitor 1 regulates ER-stress-induced ROS accumulation through the regulation of cytochrome P450 2E1.

    PubMed

    Kim, Hyung-Ryong; Lee, Geum-Hwa; Cho, Eun Yi; Chae, Soo-Wan; Ahn, Taeho; Chae, Han-Jung

    2009-04-15

    This study investigated the molecular mechanism by which Bax inhibitor 1 (BI1) abrogates the accumulation of reactive oxygen species (ROS) in the endoplasmic reticulum (ER). Electron uncoupling between NADPH-dependent cytochrome P450 reductase (NPR) and cytochrome P450 2E1 (P450 2E1) is a major source of ROS on the ER membrane. ER stress produced ROS accumulation and lipid peroxidation of the ER membrane, but BI1 reduced this accumulation. Under ER stress, expression of P450 2E1 in control cells was upregulated more than in BI1-overexpressing cells. In control cells, inhibiting P450 2E1 through chemical or siRNA approaches suppressed ROS accumulation, ER membrane lipid peroxidation and the resultant cell death after ER stress. However, it had little effect in BI1-overexpressing cells. In addition, BI1 knock down also increased ROS accumulation and expression of P450 2E1. In a reconstituted phospholipid membrane containing purified BI1, NPR and P450 2E1, BI1 dose-dependently decreased the production of ROS. BI1 bound to NPR with higher affinity than P450 2E1. Furthermore, BI1 overexpression reduced the interaction of NPR and P450 2E1, and decreased the catalytic activity of P450 2E1, suggesting that the flow of electrons from NPR to P450 2E1 can be modulated by BI1. In summary, BI1 reduces the accumulation of ROS and the resultant cell death through regulating P450 2E1. PMID:19339548

  19. Association of the insulin-like growth factor binding protein 3 (IGFBP-3) polymorphism with longevity in Chinese nonagenarians and centenarians.

    PubMed

    He, Yong-Han; Lu, Xiang; Yang, Li-Qin; Xu, Liang-You; Kong, Qing-Peng

    2014-11-01

    Human lifespan is determined greatly by genetic factors and some investigations have identified putative genes implicated in human longevity. Although some genetic loci have been associated with longevity, most of them are difficult to replicate due to ethnic differences. In this study, we analyzed the association of 18 reported gene single nucleotide polymorphisms (SNPs) with longevity in 1075 samples consisting of 567 nonagenarians/centenarians and 508 younger controls using the GenomeLab SNPstream Genotyping System. Our results confirm the association of the forkhead box O3 (FOXO3) variant (rs13217795) and the ATM serine/threonine kinase (ATM) variant (rs189037) genotypes with longevity (p=0.0075 and p=0.026, using the codominant model and recessive model, respectively). Of note is that we first revealed the association of insulin-like growth factor binding protein 3 (IGFBP-3) gene polymorphism rs11977526 with longevity in Chinese nonagenarians/centenarians (p=0.033 using the dominant model and p=0.035 using the overdominant model). The FOXO3 and IGFBP-3 form important parts of the insulin/insulin-like growth factor-1 signaling pathway (IGF-1) implicated in human longevity, and the ATM gene is involved in sensing DNA damage and reducing oxidative stress, therefore our results highlight the important roles of insulin pathway and oxidative stress in the longevity in the Chinese population. PMID:25553725

  20. Metabolic engineering of resveratrol and other longevity boosting compounds.

    SciTech Connect

    Wang, Y; Chen, H; Yu, O

    2010-09-16

    Resveratrol, a compound commonly found in red wine, has attracted many attentions recently. It is a diphenolic natural product accumulated in grapes and a few other species under stress conditions. It possesses a special ability to increase the life span of eukaryotic organisms, ranging from yeast, to fruit fly, to obese mouse. The demand for resveratrol as a food and nutrition supplement has increased significantly in recent years. Extensive work has been carried out to increase the production of resveratrol in plants and microbes. In this review, we will discuss the biosynthetic pathway of resveratrol and engineering methods to heterologously express the pathway in various organisms. We will outline the shortcuts and limitations of common engineering efforts. We will also discuss briefly the features and engineering challenges of other longevity boosting compounds.

  1. Metabolic engineering of resveratrol and other longevity boosting compounds.

    PubMed

    Wang, Yechun; Chen, Hui; Yu, Oliver

    2010-01-01

    Resveratrol, a compound commonly found in red wine, has attracted many attentions recently. It is a diphenolic natural product accumulated in grapes and a few other species under stress conditions. It possesses a special ability to increase the life span of eukaryotic organisms, ranging from yeast, to fruit fly, to obese mouse. The demand for resveratrol as a food and nutrition supplement has increased significantly in recent years. Extensive work has been carried out to increase the production of resveratrol in plants and microbes. In this review, we will discuss the biosynthetic pathway of resveratrol and engineering methods to heterologously express the pathway in various organisms. We will outline the shortcuts and limitations of common engineering efforts. We will also discuss briefly the features and engineering challenges of other longevity boosting compounds. PMID:20848556

  2. Regulation of toll like receptors in intestinal epithelial cells by stress and Toxoplasma gondii infection

    PubMed Central

    Gopal, R.; Birdsell, D.; Monroy, F. P.

    2008-01-01

    SUMMARY Intestinal epithelial cells (IECs) form a barrier between invading microorganisms and the underlying host tissues. IECs express Toll-like receptors (TLRs) that recognize specific molecular signatures on microbes which activate intracellular signaling pathways leading to production of proinflammatory cytokines and chemokines. Stress hormones play an important role in modulation of proinflammatory cytokines and downregulation of immune responses. Here we demonstrated that expression levels of TLR-2, TLR-4, TLR-9 and TLR-11 were significantly increased in mouse IECs following infection with Toxoplasma gondii on day 8 post infection. In contrast, expression of TLRs was significantly decreased in infected mice subjected to cold water stress (CWS+INF). Expression of TLR-9 and TLR-11 in the mouse MODE-K cell line was significantly increased after infection. Expression of TLR-9 and TLR-11 in cells exposed to norepinephrine (NE) and parasites was significantly decreased when compared to cells exposed to parasites only. A significant increase was observed in SIGIRR, a negative regulator of TLRs in the CWS+INF group when compared to the INF group. Stress components were able to decrease expression levels of TLRs in IECs, decrease parasite load, and increase expression of a negative regulator thereby ameliorating intestinal inflammatory responses commonly observed during per oral T. gondii infection in C57BL/6 mice. PMID:19067837

  3. Soybean GmPHD-Type Transcription Regulators Improve Stress Tolerance in Transgenic Arabidopsis Plants

    PubMed Central

    Hao, Yu-Jun; Zou, Hong-Feng; Wang, Hui-Wen; Zhao, Jing-Yun; Liu, Xue-Yi; Zhang, Wan-Ke; Ma, Biao; Zhang, Jin-Song; Chen, Shou-Yi

    2009-01-01

    Background Soybean [Glycine max (L.) Merr.] is one of the most important crops for oil and protein resource. Improvement of stress tolerance will be beneficial for soybean seed production. Principal Findings Six GmPHD genes encoding Alfin1-type PHD finger protein were identified and their expressions differentially responded to drought, salt, cold and ABA treatments. The six GmPHDs were nuclear proteins and showed ability to bind the cis-element “GTGGAG”. The N-terminal domain of GmPHD played a major role in DNA binding. Using a protoplast assay system, we find that GmPHD1 to GmPHD5 had transcriptional suppression activity whereas GmPHD6 did not have. In yeast assay, the GmPHD6 can form homodimer and heterodimer with the other GmPHDs except GmPHD2. The N-terminal plus the variable regions but not the PHD-finger is required for the dimerization. Transgenic Arabidopsis plants overexpressing the GmPHD2 showed salt tolerance when compared with the wild type plants. This tolerance was likely achieved by diminishing the oxidative stress through regulation of downstream genes. Significance These results provide important clues for soybean stress tolerance through manipulation of PHD-type transcription regulator. PMID:19789627

  4. WRKY1 regulates stomatal movement in drought-stressed Arabidopsis thaliana.

    PubMed

    Qiao, Zhu; Li, Chun-Long; Zhang, Wei

    2016-05-01

    A key response of plants to moisture stress is stomatal closure, a process mediated by the phytohormone abscisic acid (ABA). Closure is affected by changes in the turgor of the stomatal guard cell. The transcription factor WRKY1 is a part of the regulatory machinery underlying stomatal movements, and through this, in the plant's response to drought stress. The loss-of-function T-DNA insertion mutant wrky1 was particularly sensitive to ABA, with respect to both ion channel regulation and stomatal movements, and less sensitive to drought than the wild type. Complementation of the wrky1 mutant resulted in the recovery of the wild type phenotype. The WRKY1 product localized to the nucleus, and was shown able to bind to the W-box domain in the promoters of MYB2, ABCG40, DREB1A and ABI5, and thereby to control their transcription in response to drought stress or ABA treatment. WRKY1 is thought to act as a negative regulator in guard cell ABA signalling. PMID:26820136

  5. Expression of the axonal membrane glycoprotein M6a is regulated by chronic stress.

    PubMed

    Cooper, Ben; Fuchs, Eberhard; Flügge, Gabriele

    2009-01-01

    It has been repeatedly shown that chronic stress changes dendrites, spines and modulates expression of synaptic molecules. These effects all may impair information transfer between neurons. The present study shows that chronic stress also regulates expression of M6a, a glycoprotein which is localised in axonal membranes. We have previously demonstrated that M6a is a component of glutamatergic axons. The present data reveal that it is the splice variant M6a-Ib, not M6a-Ia, which is strongly expressed in the brain. Chronic stress in male rats (3 weeks daily restraint) has regional effects: quantitative in situ hybridization demonstrated that M6a-Ib mRNA in dentate gyrus granule neurons and in CA3 pyramidal neurons is downregulated, whereas M6a-Ib mRNA in the medial prefrontal cortex is upregulated by chronic stress. This is the first study showing that expression of an axonal membrane molecule is differentially affected by stress in a region-dependent manner. Therefore, one may speculate that diminished expression of the glycoprotein in the hippocampus leads to altered output in the corresponding cortical projection areas. Enhanced M6a-Ib expression in the medial prefrontal cortex (in areas prelimbic and infralimbic cortex) might be interpreted as a compensatory mechanism in response to changes in axonal projections from the hippocampus. Our findings provide evidence that in addition to alterations in dendrites and spines chronic stress also changes the integrity of axons and may thus impair information transfer even between distant brain regions. PMID:19180239

  6. The rate of metabolism as a factor determining longevity of the Saccharomyces cerevisiae yeast.

    PubMed

    Molon, Mateusz; Szajwaj, Monika; Tchorzewski, Marek; Skoczowski, Andrzej; Niewiadomska, Ewa; Zadrag-Tecza, Renata

    2016-02-01

    Despite many controversies, the yeast Saccharomyces cerevisiae continues to be used as a model organism for the study of aging. Numerous theories and hypotheses have been created for several decades, yet basic mechanisms of aging have remained unclear. Therefore, the principal aim of this work is to propose a possible mechanism leading to increased longevity in yeast. In this paper, we suggest for the first time that there is a link between decreased metabolic activity, fertility and longevity expressed as time of life in yeast. Determination of reproductive potential and total lifespan with the use of fob1Δ and sfp1Δ mutants allows us to compare the "longevity" presented as the number of produced daughters with the longevity expressed as the time of life. The results of analyses presented in this paper suggest the need for a change in the definition of longevity of yeast by taking into consideration the time parameter. The mutants that have been described as "long-lived" in the literature, such as the fob1Δ mutant, have an increased reproductive potential but live no longer than their standard counterparts. On the other hand, the sfp1Δ mutant and the wild-type strain produce a similar number of daughter cells, but the former lives much longer. Our results demonstrate a correlation between the decreased efficiency of the translational apparatus and the longevity of the sfp1Δ mutant. We suggest that a possible factor regulating the lifespan is the rate of cell metabolism. To measure the basic metabolism of the yeast cells, we used the isothermal microcalorimetry method. In the case of sfp1Δ, the flow of energy, ATP concentration, polysome profile and translational fitness are significantly lower in comparison with the wild-type strain and the fob1Δ mutant. PMID:26783001

  7. Oxidative stress and redox regulation of phospholipase D in myocardial disease.

    PubMed

    Tappia, Paramjit S; Dent, Melissa R; Dhalla, Naranjan S

    2006-08-01

    Oxidative stress may be viewed as an imbalance between reactive oxygen species (ROS) and oxidant production and the state of glutathione redox buffer and antioxidant defense system. Recently, a new paradigm of redox signaling has emerged whereby ROS and oxidants can function as intracellular signaling molecules, where ROS- and oxidant-induced death signal is converted into a survival signal. It is now known that oxidative stress is involved in cardiac hypertrophy and in the pathogenesis of cardiomyopathies, ischemic heart disease and congestive heart failure. Phospholipase D (PLD) is an important signaling enzyme in mammalian cells, including cardiomyocytes. PLD catalyzes the hydrolysis of phosphatidylcholine to produce phosphatidic acid (PA). Two mammalian PLD isozymes, PLD1 and PLD2 have been identified, characterized and cloned. The importance of PA in heart function is evident from its ability to stimulate cardiac sarcolemmal membrane and sarcoplasmic reticular Ca2+-related transport systems and to increase the intracellular concentration of free Ca2+ in adult cardiomyocytes and augment cardiac contractile activity of the normal heart. In addition, PA is also considered an important signal transducer in cardiac hypertrophy. Accordingly, this review discusses a role for redox signaling mediated via PLD in ischemic preconditioning and examines how oxidative stress affects PLD in normal hearts and during different myocardial diseases. In addition, the review provides a comparative account on the regulation of PLD activities in vascular smooth muscle cells under conditions of oxidative stress. PMID:16843818

  8. Cold tolerance in thiourea primed capsicum seedlings is associated with transcript regulation of stress responsive genes.

    PubMed

    Patade, Vikas Yadav; Khatri, Deepti; Manoj, Kamble; Kumari, Maya; Ahmed, Zakwan

    2012-12-01

    Benefits of seed priming in seedling establishment and tolerance to subsequent stress exposure are well reported. However, the molecular mechanisms underlying the priming mediated benefits are not much discovered. Results of our earlier experiments established that thiourea (TU) seed priming imparts cold tolerance to capsicum seedlings. Therefore, to understand molecular mechanisms underlying priming mediated cold stress tolerance, quantitative transcript expression of stress responsive genes involved in transcript regulation (CaCBF1A, CaCBF1B, Zinc Finger protein, CaWRKY30), osmotic adjustment (PROX1, P5CS, Osmotin), antioxidant defence (CAT2, APX, GST, GR1, Cu/Zn SOD, Mn SOD, Fe SOD), signaling (Annexin), movement of solutes and water (CaPIP1), and metabolite biosynthesis through phenylpropanoid pathway (CAH) was studied in response to cold (4 °C; 4 and 24 h) stress in seedlings grown from the TU primed, hydroprimed and unsoaked seeds. The transcript expression of CaWRKY30, PROX1, Osmotin, Cu/Zn SOD and CAH genes was either higher or induced earlier on cold exposure in thiourea priming than that of hydroprimed and unsoaked over the respective unstressed controls. The results thus suggest that the TU priming modulate expression of these genes thereby imparting cold tolerance in capsicum seedlings. PMID:23053959

  9. RTP801/REDD1: a stress coping regulator that turns into a troublemaker in neurodegenerative disorders

    PubMed Central

    Canal, Mercè; Romaní-Aumedes, Joan; Martín-Flores, Núria; Pérez-Fernández, Víctor; Malagelada, Cristina

    2014-01-01

    Mechanistic target of Rapamycin (mTOR) pathway regulates essential processes directed to preserve cellular homeostasis, such as cell growth, proliferation, survival, protein synthesis and autophagy. Importantly, mTOR pathway deregulation has been related to many diseases. Indeed, it has become a hallmark in neurodegenerative disorders, since a fine-tuned regulation of mTOR activities is crucial for neuron function and survival. RTP801/REDD1/Dig2 has become one of the most puzzling regulators of mTOR. Although the mechanism is not completely understood, RTP801 inactivates mTOR and Akt via the tuberous sclerosis complex (TSC1/TSC2) in many cellular contexts. Intriguingly, RTP801 protects dividing cells from hypoxia or H2O2-induced apoptosis, while it sensitizes differentiated cells to stress. Based on experimental models of Parkinson’s disease (PD), it has been proposed that at early stages of the disease, stress-induced RTP801 upregulation contributes to mTOR repression, in an attempt to maintain cell function and viability. However, if RTP801 elevation is sustained, it leads to neuron cell death by a sequential inhibition of mTOR and Akt. Here, we will review RTP801 deregulation of mTOR in a context of PD and other neurodegenerative disorders. PMID:25324725

  10. Genetics of glucocorticoid regulation and posttraumatic stress disorder--What do we know?

    PubMed

    Castro-Vale, Ivone; van Rossum, Elisabeth F C; Machado, José Carlos; Mota-Cardoso, Rui; Carvalho, Davide

    2016-04-01

    CASTRO-VALE, I., E.F.C. van Rossum, J.C. Machado, R. Mota-Cardoso and D. Carvalho. Genetics of glucocorticoid regulation and posttraumatic stress disorder-What do we know? NEUROSCI. BIOBEHAV. REV. 43 (1) XXX-XXX, 2014 - Posttraumatic stress disorder (PTSD) develops in a small proportion of those who have been exposed to a traumatic event. Genetic factors are estimated to be responsible for 30% of the variance in PTSD risk. Dysfunction of the hypothalamic-pituitary-adrenal (HPA)-axis in PTSD has been found, particularly hypersensitivity of the glucocorticoid receptor (GR). In this review we aim to understand the genetic factors that influence glucocorticoid function in PTSD. Glucocorticoid action is regulated by a corticotrophin-releasing hormone, arginine vasopressin (AVP)/oxytocin pathway, GR, and regulators such as co-chaperone FKBP5. Single nucleotide polymorphisms (SNPs) in the GR gene, CRHR1 gene and FKBP5 gene affect HPA-axis sensitivity. The GR gene SNP BclI has been associated with hypersensitivity to glucocorticoids and PTSD symptoms. FKBP5 gene SNPs interacted with childhood adversity to moderate PTSD risk and in particular, the rs9470080 SNP was independently associated with lifetime PTSD. SNPs in the CRHR1 gene were also associated with PTSD risk. Gene-environment interaction studies have highlighted the importance of multifactorial vulnerability in PTSD, with epigenetic mechanisms contributing to the equation. PMID:26872620

  11. Two Spx Regulators Modulate Stress Tolerance and Virulence in Streptococcus suis Serotype 2

    PubMed Central

    Zheng, Chengkun; Xu, Jiali; Li, Jinquan; Hu, Luohong; Xia, Jiandong; Fan, Jingyan; Guo, Weina; Chen, Huanchun; Bei, Weicheng

    2014-01-01

    Streptococcus suis serotype 2 is an important zoonotic pathogen causing severe infections in pigs and humans. The pathogenesis of S. suis 2 infections, however, is still poorly understood. Spx proteins are a group of global regulators involved in stress tolerance and virulence. In this study, we characterized two orthologs of the Spx regulator, SpxA1 and SpxA2 in S. suis 2. Two mutant strains (ΔspxA1 and ΔspxA2) lacking the spx genes were constructed. The ΔspxA1 and ΔspxA2 mutants displayed different phenotypes. ΔspxA1 exhibited impaired growth in the presence of hydrogen peroxide, while ΔspxA2 exhibited impaired growth in the presence of SDS and NaCl. Both mutants were defective in medium lacking newborn bovine serum. Using a murine infection model, we demonstrated that the abilities of the mutant strains to colonize the tissues were significantly reduced compared to that of the wild-type strain. The mutant strains also showed a decreased level of survival in pig blood. Microarray analysis revealed a global regulatory role for SpxA1 and SpxA2. Furthermore, we demonstrated for the first time that Spx is involved in triggering the host inflammatory response. Collectively, our data suggest that SpxA1 and SpxA2 are global regulators that are implicated in stress tolerance and virulence in S. suis 2. PMID:25264876

  12. Microcystin Production and Regulation under Nutrient Stress Conditions in Toxic Microcystis Strains

    PubMed Central

    Pimentel, Juliana S. M.

    2014-01-01

    Microcystin is a common and well-known cyanobacterial toxin whose intracellular role is still under investigation. Increasing knowledge on microcystin gene expression and regulation can contribute to the understanding of its putative cellular function. In this work, reverse transcription-quantitative PCR (RT-qPCR) was used to investigate the transcriptional response of the mcyD gene to nitrogen (nitrate and ammonium) and phosphorus limitation in two toxic Microcystis strains. The existence of a direct correlation between transcripts of mcyD and ntcA genes was also identified. In previous studies, NtcA (global nitrogen regulator) has been described as a potential component in the control of microcystin biosynthesis. This research showed that stress agents linked to nutrient deprivation could lead to a significant increase of microcystin production in both strains studied. The more toxic strain proved to be more resistant to nutrient limitation. The similar outcomes of mcyD regulation observed for all nutrients suggest that this response can be linked to oxidative stress of cells undergoing adverse growth conditions. PMID:25038094

  13. Topological characteristics of target genes regulated by abiotic-stress-responsible miRNAs in a rice interactome network.

    PubMed

    Zhang, Linzhong; Xuan, Hongdong; Zuo, Yongchun; Xu, Gaojian; Wang, Ping; Song, Youhong; Zhang, Shihua

    2016-05-01

    A great number of microRNAs (miRNAs) have been identified in responding and acting in gene regulatory networks associated with plant tolerance to abiotic stress conditions, such as drought, salinity, and high temperature. The topological exploration of target genes regulated by abiotic-stress-responsible miRNAs (ASRmiRs) in a network facilitates to discover the molecular basis of plant abiotic stress response. This study was based on the staple food rice (Oryza sativa) in which ASRmiRs were manually curated. After having compared the topological properties of target genes (stress-miR-targets) with those (non-stress-miR-targets) not regulated by ASRmiRs in a rice interactome network, we found that stress-miR-targets exhibited distinguishable topological properties. The interaction probability analysis and k-core decomposition showed that stress-miR-targets preferentially interacted with non-stress-miR-targets and located at the peripheral positions in the network. Our results indicated an obvious topological distinction between the two types of genes, reflecting the specific mechanisms of action of stress-miR-targets in rice abiotic stress response. Also, the results may provide valuable clues to elucidate molecular mechanisms of crop response to abiotic stress. PMID:26830287

  14. Stress-induced and epigenetic-mediated maize transcriptome regulation study by means of transcriptome reannotation and differential expression analysis.

    PubMed

    Forestan, Cristian; Aiese Cigliano, Riccardo; Farinati, Silvia; Lunardon, Alice; Sanseverino, Walter; Varotto, Serena

    2016-01-01

    Plant's response and adaptation to abiotic stresses involve sophisticated genetic and epigenetic regulatory systems. To obtain a global view of molecular response to osmotic stresses, including the non-coding portion of genome, we conducted a total leaf transcriptome analysis on maize plants subjected to prolonged drought and salt stresses. Stress application to both B73 wild type and the epiregulator mutant rpd1-1/rmr6 allowed dissection of the epigenetic component of stress response. Coupling total RNA-Seq and transcriptome re-assembly we annotated thousands of new maize transcripts, together with 13,387 lncRNAs that may play critical roles in regulating gene expression. Differential expression analysis revealed hundreds of genes modulated by long-term stress application, including also many lncRNAs and transposons specifically induced by stresses. The amplitude and dynamic of the stress-modulated gene sets are very different between B73 and rpd1-1/rmr6 mutant plants, as result of stress-like effect on genome regulation caused by the mutation itself, which activates many stress-related genes even in control condition. The analyzed extensive set of total RNA-Seq data, together with the improvement of the transcriptome and the identification of the non-coding portion of the transcriptome give a revealing insight into the genetic and epigenetic mechanism responsible for maize molecular response to abiotic stresses. PMID:27461139

  15. Stress-induced and epigenetic-mediated maize transcriptome regulation study by means of transcriptome reannotation and differential expression analysis

    PubMed Central

    Forestan, Cristian; Aiese Cigliano, Riccardo; Farinati, Silvia; Lunardon, Alice; Sanseverino, Walter; Varotto, Serena

    2016-01-01

    Plant’s response and adaptation to abiotic stresses involve sophisticated genetic and epigenetic regulatory systems. To obtain a global view of molecular response to osmotic stresses, including the non-coding portion of genome, we conducted a total leaf transcriptome analysis on maize plants subjected to prolonged drought and salt stresses. Stress application to both B73 wild type and the epiregulator mutant rpd1-1/rmr6 allowed dissection of the epigenetic component of stress response. Coupling total RNA-Seq and transcriptome re-assembly we annotated thousands of new maize transcripts, together with 13,387 lncRNAs that may play critical roles in regulating gene expression. Differential expression analysis revealed hundreds of genes modulated by long-term stress application, including also many lncRNAs and transposons specifically induced by stresses. The amplitude and dynamic of the stress-modulated gene sets are very different between B73 and rpd1-1/rmr6 mutant plants, as result of stress-like effect on genome regulation caused by the mutation itself, which activates many stress-related genes even in control condition. The analyzed extensive set of total RNA-Seq data, together with the improvement of the transcriptome and the identification of the non-coding portion of the transcriptome give a revealing insight into the genetic and epigenetic mechanism responsible for maize molecular response to abiotic stresses. PMID:27461139

  16. Does rumination mediate the relationship between emotion regulation ability and posttraumatic stress disorder?

    PubMed Central

    Ehring, Thomas; Ehlers, Anke

    2014-01-01

    Background and objectives Trauma-related rumination has been suggested to be involved in the maintenance of posttraumatic stress disorder (PTSD). This view has empirically been supported by extensive evidence using cross-sectional, prospective, and experimental designs. However, it is unclear why trauma survivors engage in rumination despite its negative consequences. The current study aimed to explore the hypothesis that low emotion regulation ability underlies trauma-related rumination. Methods Emotion regulation ability and trauma-related rumination were assessed in 93 road traffic accident survivors 2 weeks post-trauma. In addition, symptom levels of PTSD were assessed at 2 weeks as well as 1, 3, and 6 months follow-up. Results Emotion regulation ability was significantly related to trauma-related rumination as well as levels of PTSD symptoms. In addition, the association between low emotion regulation ability and PTSD was mediated by rumination. Conclusions The findings support the view that rumination is used as a dysfunctional emotion regulation strategy by trauma survivors. PMID:25206955

  17. Jasmonic acid interacts with abscisic acid to regulate plant responses to water stress conditions

    PubMed Central

    de Ollas, Carlos; Arbona, Vicent; Gómez-Cadenas, Aurelio

    2015-01-01

    Phytohormones are key players in signaling environmental stress conditions. Hormone profiling together with proline accumulation were studied in leaves and roots of different mutant lines of Arabidopsis. Regulation of proline accumulation in this system seems complex and JA-deficient (jar1-1) and JA-insensitive (jai1) lines accumulating high levels of proline despite their very low ABA levels seems to discard an ABA-dependent response. However, the pattern of proline accumulation in jai1 seedlings parallels that of ABA. Under stress conditions, there is an opposite pattern of ABA accumulation in roots of jar1-1/coi1-16 (in which ABA only slightly increase) and jai1 (in which ABA increase is even higher than in WT plants). This also makes JA-ABA crosstalk complex and discards any lineal pathway that could explain this hormonal interaction. PMID:26340066

  18. Stress-dependent regulation of 13-lipoxygenases and 13-hydroperoxide lyase in olive fruit mesocarp.

    PubMed

    Padilla, María N; Hernández, M Luisa; Sanz, Carlos; Martínez-Rivas, José M

    2014-06-01

    The effect of different environmental stresses on the expression and enzyme activity levels of 13-lipoxygenases (13-LOX) and 13-hydroperoxide lyase (13-HPL) and on the volatile compounds synthesized by their sequential action has been studied in the mesocarp tissue of olive fruit from the Picual and Arbequina cultivars. The results showed that temperature, light, wounding and water regime regulate olive 13-LOXs and 13-HPL genes at transcriptional level. Low temperature and wounding brought about an increase in LOX and HPL enzyme activities. A very slight increase in the total content of six straight-chain carbons (C6) volatile compounds was also observed in the case of low temperature and wounding treatments. The physiological roles of 13-LOXs and 13-HPL in the olive fruit stress response are discussed. PMID:24629805

  19. RSS1 regulates the cell cycle and maintains meristematic activity under stress conditions in rice

    PubMed Central

    Ogawa, Daisuke; Abe, Kiyomi; Miyao, Akio; Kojima, Mikiko; Sakakibara, Hitoshi; Mizutani, Megumi; Morita, Haruka; Toda, Yosuke; Hobo, Tokunori; Sato, Yutaka; Hattori, Tsukaho; Hirochika, Hirohiko; Takeda, Shin

    2011-01-01

    Plant growth and development are sustained by continuous cell division in the meristems, which is perturbed by various environmental stresses. For the maintenance of meristematic functions, it is essential that cell division be coordinated with cell differentiation. However, it is unknown how the proliferative activities of the meristems and the coordination between cell division and differentiation are maintained under stressful conditions. Here we show that a rice protein, RSS1, whose stability is controlled by cell cycle phases, contributes to the vigour of meristematic cells and viability under salinity conditions. These effects of RSS1 are exerted by regulating the G1–S transition, possibly through an interaction of RSS1 with protein phosphatase 1, and are mediated by the phytohormone, cytokinin. RSS1 is conserved widely in plant lineages, except eudicots, suggesting that RSS1-dependent mechanisms might have been adopted in specific lineages during the evolutionary radiation of angiosperms. PMID:21505434

  20. Jagn1 Is Induced in Response to ER Stress and Regulates Proinsulin Biosynthesis

    PubMed Central

    Nosak, Courtney; Silva, Pamuditha N.; Sollazzo, Pietro; Moon, Kyung-Mee; Odisho, Tanya; Foster, Leonard J.; Rocheleau, Jonathan V.; Volchuk, Allen

    2016-01-01

    The Jagn1 protein was indentified in a SILAC proteomic screen of proteins that are increased in insulinoma cells expressing a folding-deficient proinsulin. Jagn1 mRNA was detected in primary rodent islets and in insulinoma cell lines and the levels were increased in response to ER stress. The function of Jagn1 was assessed in insulinoma cells by both knock-down and overexpression approaches. Knock-down of Jagn1 caused an increase in glucose-stimulated insulin secretion resulting from an increase in proinsulin biosynthesis. In contrast, overexpression of Jagn1 in insulinoma cells resulted in reduced cellular proinsulin and insulin levels. Our results identify a novel role for Jagn1 in regulating proinsulin biosynthesis in pancreatic β-cells. Under ER stress conditions Jagn1 is induced which might contribute to reducing proinsulin biosynthesis, in part by helping to relieve the protein folding load in the ER in an effort to restore ER homeostasis. PMID:26882284

  1. Roles of Chinese herbal medicines in ischemic heart diseases (IHD) by regulating oxidative stress.

    PubMed

    Wang, Dawei; Wang, Jin; Liu, Yuntao; Zhao, Zhen; Liu, Qing

    2016-10-01

    Ischemic heart disease (IHD) basing on atherosclerosis (AS) is known as a top killer for decades. Oxidative stress, representing excessive oxidation and insufficient elimination, has been proved to be a critical molecular mechanism of IHD and accompanying myocardium dysfunction. Therefore, anti-oxidation therapy may be efficient. Chinese herbal medicine, including extractive compounds, decoctions, patent drugs, and injections, has shown its enormous potential in prevention and treatment of IHD as an effective antioxidant in experimental studies. The aim of this review is to highlight recent studies of Chinese herbal medicine in regulating oxidative stress in IHD. These studies represent recent progress of IHD treatment and indicate the possible pathways and target spots of Chinese herbal medicine. PMID:27390948

  2. Jasmonic acid interacts with abscisic acid to regulate plant responses to water stress conditions.

    PubMed

    de Ollas, Carlos; Arbona, Vicent; Gómez-Cadenas, Aurelio

    2015-01-01

    Phytohormones are key players in signaling environmental stress conditions. Hormone profiling together with proline accumulation were studied in leaves and roots of different mutant lines of Arabidopsis. Regulation of proline accumulation in this system seems complex and JA-deficient (jar1-1) and JA-insensitive (jai1) lines accumulating high levels of proline despite their very low ABA levels seems to discard an ABA-dependent response. However, the pattern of proline accumulation in jai1 seedlings parallels that of ABA. Under stress conditions, there is an opposite pattern of ABA accumulation in roots of jar1-1/coi1-16 (in which ABA only slightly increase) and jai1 (in which ABA increase is even higher than in WT plants). This also makes JA-ABA crosstalk complex and discards any lineal pathway that could explain this hormonal interaction. PMID:26340066

  3. A-kinase anchoring proteins: molecular regulators of the cardiac stress response.

    PubMed

    Diviani, Dario; Maric, Darko; Pérez López, Irene; Cavin, Sabrina; Del Vescovo, Cosmo D

    2013-04-01

    In response to stress or injury the heart undergoes a pathological remodeling process, associated with hypertrophy, cardiomyocyte death and fibrosis, that ultimately causes cardiac dysfunction and heart failure. It has become increasingly clear that signaling events associated with these pathological cardiac remodeling events are regulated by scaffolding and anchoring proteins, which allow coordination of pathological signals in space and time. A-kinase anchoring proteins (AKAPs) constitute a family of functionally related proteins that organize multiprotein signaling complexes that tether the cAMP-dependent protein kinase (PKA) as well as other signaling enzymes to ensure integration and processing of multiple signaling pathways. This review will discuss the role of AKAPs in the cardiac response to stress. Particular emphasis will be given to the adaptative process associated with cardiac hypoxia as well as the remodeling events linked to cardiac hypertrophy and heart failure. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Cardiac Pathways of Differentiation, Metabolism and Contraction. PMID:22889610

  4. A Study of the Relationship between Cognitive Emotion Regulation, Optimism, and Perceived Stress among Selected Teachers in Lutheran Schools

    ERIC Educational Resources Information Center

    Gliebe, Sudi Kate

    2012-01-01

    Problem: The problem of this study was to determine the relationship between perceived stress, as measured by the Perceived Stress Scale (PSS), and a specific set of predictor variables among selected teachers in Lutheran schools in the United States. These variables were cognitive emotion regulation strategies (positive reappraisal and…

  5. Repressors Nrg1 and Nrg2 regulate a set of stress-responsive genes in Saccharomyces cerevisiae.

    PubMed

    Vyas, Valmik K; Berkey, Cristin D; Miyao, Takenori; Carlson, Marian

    2005-11-01

    The yeast Saccharomyces cerevisiae responds to environmental stress by rapidly altering the expression of large sets of genes. We report evidence that the transcriptional repressors Nrg1 and Nrg2 (Nrg1/Nrg2), which were previously implicated in glucose repression, regulate a set of stress-responsive genes. Genome-wide expression analysis identified 150 genes that were upregulated in nrg1Delta nrg2Delta double mutant cells, relative to wild-type cells, during growth in glucose. We found that many of these genes are regulated by glucose repression. Stress response elements (STREs) and STRE-like elements are overrepresented in the promoters of these genes, and a search of available expression data sets showed that many are regulated in response to a variety of environmental stress signals. In accord with these findings, mutation of NRG1 and NRG2 enhanced the resistance of cells to salt and oxidative stress and decreased tolerance to freezing. We present evidence that Nrg1/Nrg2 not only contribute to repression of target genes in the absence of stress but also limit induction in response to salt stress. We suggest that Nrg1/Nrg2 fine-tune the regulation of a set of stress-responsive genes. PMID:16278455

  6. Role of Central Glucagon-like Peptide-1 in Stress Regulation

    PubMed Central

    Ghosal, Sriparna; Myers, Brent; Herman, James P.

    2013-01-01

    Glucagon-like peptide 1 (GLP-1) is best known as an incretin hormone, secreted from L cells in the intestine in response to nutrient ingestion to stimulate glucose-dependent insulin secretion. However, GLP-1 is also expressed in neurons, and plays a major role in regulation of homeostatic function within the central nervous system (CNS). This review summarizes our current state of knowledge on the role GLP-1 plays in neural coordination of the organismal stress response. In brain, the primary locus of GLP-1 production is in the caudal nucleus of the solitary tract (NTS) and the ventrolateral medulla of the hindbrain. GLP-1 immunoreactive fibers directly innervate hypophysiotrophic corticotropin-releasing hormone (CRH) neurons in the hypothalamic paraventricular nucleus (PVN), placing GLP-1 in prime position to integrate hypothalamo-pituitary-adrenocortical responses. Exogenous central GLP-1 activates HPA axis stress responses, and responses to a variety of stressors can be blocked by a GLP-1 receptor (GLP-1R) antagonist, confirming an excitatory role in glucocorticoid secretion. In addition, central infusion of GLP-1R agonist increases heart rate and blood pressure, and activates hypothalamic and brainstem neurons innervating sympathetic preganglionic neurons, suggesting a sympathoexcitatory role of GLP-1 in the CNS. Bioavailability of preproglucagon (PPG) mRNA and GLP-1 peptide is reduced by exogenous or endogenous glucocorticoid secretion, perhaps as a mechanism to reduce GLP-1-mediated stress excitation. Altogether, the data suggest that GLP-1 plays a key role in activation of stress responses, which may be connected with its role in central regulation of energy homeostasis. PMID:23623992

  7. Pur-alpha regulates cytoplasmic stress granule dynamics and ameliorates FUS toxicity.

    PubMed

    Daigle, J Gavin; Krishnamurthy, Karthik; Ramesh, Nandini; Casci, Ian; Monaghan, John; McAvoy, Kevin; Godfrey, Earl W; Daniel, Dianne C; Johnson, Edward M; Monahan, Zachary; Shewmaker, Frank; Pasinelli, Piera; Pandey, Udai Bhan

    2016-04-01

    Amyotrophic lateral sclerosis is characterized by progressive loss of motor neurons in the brain and spinal cord. Mutations in several genes, including FUS, TDP43, Matrin 3, hnRNPA2 and other RNA-binding proteins, have been linked to ALS pathology. Recently, Pur-alpha, a DNA/RNA-binding protein was found to bind to C9orf72 repeat expansions and could possibly play a role in the pathogenesis of ALS. When overexpressed, Pur-alpha mitigates toxicities associated with Fragile X tumor ataxia syndrome (FXTAS) and C9orf72 repeat expansion diseases in Drosophila and mammalian cell culture models. However, the function of Pur-alpha in regulating ALS pathogenesis has not been fully understood. We identified Pur-alpha as a novel component of cytoplasmic stress granules (SGs) in ALS patient cells carrying disease-causing mutations in FUS. When cells were challenged with stress, we observed that Pur-alpha co-localized with mutant FUS in ALS patient cells and became trapped in constitutive SGs. We also found that FUS physically interacted with Pur-alpha in mammalian neuronal cells. Interestingly, shRNA-mediated knock down of endogenous Pur-alpha significantly reduced formation of cytoplasmic stress granules in mammalian cells suggesting that Pur-alpha is essential for the formation of SGs. Furthermore, ectopic expression of Pur-alpha blocked cytoplasmic mislocalization of mutant FUS and strongly suppressed toxicity associated with mutant FUS expression in primary motor neurons. Our data emphasizes the importance of stress granules in ALS pathogenesis and identifies Pur-alpha as a novel regulator of SG dynamics. PMID:26728149

  8. Quantitative iTRAQ-based proteomic analysis of phosphoproteins and ABA-regulated phosphoproteins in maize leaves under osmotic stress

    PubMed Central

    Hu, Xiuli; Li, Nana; Wu, Liuji; Li, Chunqi; Li, Chaohai; Zhang, Li; Liu, Tianxue; Wang, Wei

    2015-01-01

    Abscisic acid (ABA) regulates various developmental processes and stress responses in plants. Protein phosphorylation/dephosphorylation is a central post-translational modification (PTM) in ABA signaling. However, the phosphoproteins regulated by ABA under osmotic stress remain unknown in maize. In this study, maize mutant vp5 (deficient in ABA biosynthesis) and wild-type Vp5 were used to identify leaf phosphoproteins regulated by ABA under osmotic stress. Up to 4052 phosphopeptides, corresponding to 3017 phosphoproteins, were identified by Multiplex run iTRAQ-based quantitative proteomic and LC-MS/MS methods. The 4052 phosphopeptides contained 5723 non-redundant phosphosites; 512 phosphopeptides (379 in Vp5, 133 in vp5) displayed at least a 1.5-fold change of phosphorylation level under osmotic stress, of which 40 shared common in both genotypes and were differentially regulated by ABA. Comparing the signaling pathways involved in vp5 response to osmotic stress and those that in Vp5, indicated that ABA played a vital role in regulating these pathways related to mRNA synthesis, protein synthesis and photosynthesis. Our results provide a comprehensive dataset of phosphopeptides and phosphorylation sites regulated by ABA in maize adaptation to osmotic stress. This will be helpful to elucidate the ABA-mediate mechanism of maize endurance to drought by triggering phosphorylation or dephosphorylation cascades. PMID:26503333

  9. Cyclic AMP Receptor Protein Acts as a Transcription Regulator in Response to Stresses in Deinococcus radiodurans

    PubMed Central

    Wang, Jiali; Liu, Chengzhi; Lu, Huizhi; Liu, Mengjia; Zhao, Ye; Tian, Bing; Wang, Liangyan; Hua, Yuejin

    2016-01-01

    The cyclic AMP receptor protein family of transcription factors regulates various metabolic pathways in bacteria, and also play roles in response to environmental changes. Here, we identify four homologs of the CRP family in Deinococcus radiodurans, one of which tolerates extremely high levels of oxidative stress and DNA-damaging reagents. Transcriptional levels of CRP were increased under hydrogen peroxide (H2O2) treatment during the stationary growth phase, indicating that CRPs function in response to oxidative stress. By constructing all CRP single knockout mutants, we found that the dr0997 mutant showed the lowest tolerance toward H2O2, ultraviolet radiation, ionizing radiation, and mitomycin C, while the phenotypes of the dr2362, dr0834, and dr1646 mutants showed slight or no significant differences from those of the wild-type strain. Taking advantage of the conservation of the CRP-binding site in many bacteria, we found that transcription of 18 genes, including genes encoding chromosome-partitioning protein (dr0998), Lon proteases (dr0349 and dr1974), NADH-quinone oxidoreductase (dr1506), thiosulfate sulfurtransferase (dr2531), the DNA repair protein UvsE (dr1819), PprA (dra0346), and RecN (dr1447), are directly regulated by DR0997. Quantitative real-time polymerase chain reaction (qRT-PCR) analyses showed that certain genes involved in anti-oxidative responses, DNA repair, and various cellular pathways are transcriptionally attenuated in the dr0997 mutant. Interestingly, DR0997 also regulate the transcriptional levels of all CRP genes in this bacterium. These data suggest that DR0997 contributes to the extreme stress resistance of D. radiodurans via its regulatory role in multiple cellular pathways, such as anti-oxidation and DNA repair pathways. PMID:27182600

  10. Salt Stress and Ethylene Antagonistically Regulate Nucleocytoplasmic Partitioning of COP1 to Control Seed Germination.

    PubMed

    Yu, Yanwen; Wang, Juan; Shi, Hui; Gu, Juntao; Dong, Jingao; Deng, Xing Wang; Huang, Rongfeng

    2016-04-01

    Seed germination, a critical stage initiating the life cycle of a plant, is severely affected by salt stress. However, the underlying mechanism of salt inhibition of seed germination (SSG) is unclear. Here, we report that the Arabidopsis (Arabidopsis thaliana) CONSTITUTIVE PHOTOMORPHOGENESIS1 (COP1) counteracts SSG Genetic assays provide evidence that SSG in loss of function of the COP1 mutant was stronger than this in the wild type. A GUS-COP1 fusion was constitutively localized to the nucleus in radicle cells. Salt treatment caused COP1 to be retained in the cytosol, but the addition of ethylene precursor 1-aminocyclopropane-1-carboxylate had the reverse effect on the translocation of COP1 to the nucleus, revealing that ethylene and salt exert opposite regulatory effects on the localization of COP1 in germinating seeds. However, loss of function of the ETHYLENE INSENSITIVE3 (EIN3) mutant impaired the ethylene-mediated rescue of the salt restriction of COP1 to the nucleus. Further research showed that the interaction between COP1 and LONG HYPOCOTYL5 (HY5) had a role in SSG Correspondingly, SSG in loss of function of HY5 was suppressed. Biochemical detection showed that salt promoted the stabilization of HY5, whereas ethylene restricted its accumulation. Furthermore, salt treatment stimulated and ethylene suppressed transcription of ABA INSENSITIVE5 (ABI5), which was directly transcriptionally regulated by HY5. Together, our results reveal that salt stress and ethylene antagonistically regulate nucleocytoplasmic partitioning of COP1, thereby controlling Arabidopsis seed germination via the COP1-mediated down-regulation of HY5 and ABI5. These findings enhance our understanding of the stress response and have great potential for application in agricultural production. PMID:26850275

  11. Seasonal programming of adult longevity in Ukraine

    NASA Astrophysics Data System (ADS)

    Vaiserman, A. M.; Collinson, A. C.; Koshel, N. M.; Belaja, I. I.; Voitenko, V. P.

    2002-09-01

    Longevity was significantly associated with season of birth in 101,634 individuals who died in Kiev during the period 1990-2000. The relationship between age at death and month of birth showed a very similar pattern for both men and women. Mean values for the age at death were lowest for subjects born in April-July, and highest for individuals born at the beginning and end of the year. Minimum and maximum ages at death, analysed according to month of birth, differed by 2.6 years in men and 2.3 years in women. For all major causes of death causes, the mean age at death for persons born in the fourth quarter was the highest. These results suggest that, in this population, longevity is affected by prenatal or early postnatal seasonal factors. This is consistent with the hypothesis that the rate of ageing may be programmed in response to environmental influences at critical periods of early development.

  12. Longevity of emplacement drift ground support materials

    SciTech Connect

    Tang, David

    2000-04-01

    The purpose of this analysis is to evaluate the factors affecting the longevity of emplacement drift ground support materials and to develop a basis for the selection of materials for ground support that will function throughout the preclosure period of a potential repository at Yucca Mountain. The Development Plan (DP) for this analysis is given in Longevity of Emplacement Drift Ground Support Materials (CRWMS M and O 1999a). The objective of this analysis is to update the previous analysis (CRWMS M and O 2000a) to account for related changes in the Ground Control System Description Document (CRWMS M and O 2000b), the Monitored Geologic Repository Project Description Document (CRWMS M and O 1999b), and in environmental conditions, and to provide updated information on candidate ground support materials.

  13. Rice Ribosomal Protein Large Subunit Genes and Their Spatio-temporal and Stress Regulation

    PubMed Central

    Moin, Mazahar; Bakshi, Achala; Saha, Anusree; Dutta, Mouboni; Madhav, Sheshu M.; Kirti, P. B.

    2016-01-01

    Ribosomal proteins (RPs) are well-known for their role in mediating protein synthesis and maintaining the stability of the ribosomal complex, which includes small and large subunits. In the present investigation, in a genome-wide survey, we predicted that the large subunit of rice ribosomes is encoded by at least 123 genes including individual gene copies, distributed throughout the 12 chromosomes. We selected 34 candidate genes, each having 2–3 identical copies, for a detailed characterization of their gene structures, protein properties, cis-regulatory elements and comprehensive expression analysis. RPL proteins appear to be involved in interactions with other RP and non-RP proteins and their encoded RNAs have a higher content of alpha-helices in their predicted secondary structures. The majority of RPs have binding sites for metal and non-metal ligands. Native expression profiling of 34 ribosomal protein large (RPL) subunit genes in tissues covering the major stages of rice growth shows that they are predominantly expressed in vegetative tissues and seedlings followed by meiotically active tissues like flowers. The putative promoter regions of these genes also carry cis-elements that respond specifically to stress and signaling molecules. All the 34 genes responded differentially to the abiotic stress treatments. Phytohormone and cold treatments induced significant up-regulation of several RPL genes, while heat and H2O2 treatments down-regulated a majority of them. Furthermore, infection with a bacterial pathogen, Xanthomonas oryzae, which causes leaf blight also induced the expression of 80% of the RPL genes in leaves. Although the expression of RPL genes was detected in all the tissues studied, they are highly responsive to stress and signaling molecules indicating that their encoded proteins appear to have roles in stress amelioration besides house-keeping. This shows that the RPL gene family is a valuable resource for manipulation of stress tolerance in

  14. Rice Ribosomal Protein Large Subunit Genes and Their Spatio-temporal and Stress Regulation.

    PubMed

    Moin, Mazahar; Bakshi, Achala; Saha, Anusree; Dutta, Mouboni; Madhav, Sheshu M; Kirti, P B

    2016-01-01

    Ribosomal proteins (RPs) are well-known for their role in mediating protein synthesis and maintaining the stability of the ribosomal complex, which includes small and large subunits. In the present investigation, in a genome-wide survey, we predicted that the large subunit of rice ribosomes is encoded by at least 123 genes including individual gene copies, distributed throughout the 12 chromosomes. We selected 34 candidate genes, each having 2-3 identical copies, for a detailed characterization of their gene structures, protein properties, cis-regulatory elements and comprehensive expression analysis. RPL proteins appear to be involved in interactions with other RP and non-RP proteins and their encoded RNAs have a higher content of alpha-helices in their predicted secondary structures. The majority of RPs have binding sites for metal and non-metal ligands. Native expression profiling of 34 ribosomal protein large (RPL) subunit genes in tissues covering the major stages of rice growth shows that they are predominantly expressed in vegetative tissues and seedlings followed by meiotically active tissues like flowers. The putative promoter regions of these genes also carry cis-elements that respond specifically to stress and signaling molecules. All the 34 genes responded differentially to the abiotic stress treatments. Phytohormone and cold treatments induced significant up-regulation of several RPL genes, while heat and H2O2 treatments down-regulated a majority of them. Furthermore, infection with a bacterial pathogen, Xanthomonas oryzae, which causes leaf blight also induced the expression of 80% of the RPL genes in leaves. Although the expression of RPL genes was detected in all the tissues studied, they are highly responsive to stress and signaling molecules indicating that their encoded proteins appear to have roles in stress amelioration besides house-keeping. This shows that the RPL gene family is a valuable resource for manipulation of stress tolerance in rice

  15. Environmental Temperature Differentially Modulates C. elegans Longevity through a Thermosensitive TRP Channel.

    PubMed

    Zhang, Bi; Xiao, Rui; Ronan, Elizabeth A; He, Yongqun; Hsu, Ao-Lin; Liu, Jianfeng; Xu, X Z Shawn

    2015-06-01

    Temperature profoundly affects aging in both poikilotherms and homeotherms. A general belief is that lower temperatures extend lifespan, whereas higher temperatures shorten it. Although this "temperature law" is widely accepted, it has not been extensively tested. Here, we systematically evaluated the role of temperature in lifespan regulation in C. elegans. We found that, although exposure to low temperatures at the adult stage prolongs lifespan, low-temperature treatment at the larval stage surprisingly reduces lifespan. Interestingly, this differential effect of temperature on longevity in larvae and adults is mediated by the same thermosensitive TRP channel TRPA-1 that signals to the transcription factor DAF-16/FOXO. DAF-16/FOXO and TRPA-1 act in larva to shorten lifespan but extend lifespan in adulthood. DAF-16/FOXO differentially regulates gene expression in larva and adult in a temperature-dependent manner. Our results uncover complexity underlying temperature modulation of longevity, demonstrating that temperature differentially regulates lifespan at different stages of life. PMID:26027928

  16. Predictors of Exceptional Longevity: Effects of Early-Life and Midlife Conditions, and Familial Longevity

    PubMed Central

    Gavrilov, Leonid A.; Gavrilova, Natalia S.

    2015-01-01

    Knowledge of strong predictors of mortality and longevity is very important for actuarial science and practice. Earlier studies found that parental characteristics as well as early-life conditions and midlife environment play a significant role in survival to advanced ages. However, little is known about the simultaneous effects of these three factors on longevity. This ongoing study attempts to fill this gap by comparing centenarians born in the United States in 1890–1891 with peers born in the same years who died at age 65. The records for centenarians and controls were taken from computerized family histories, which were then linked to 1900 and 1930 U.S. censuses. As a result of this linkage procedure, 765 records of confirmed centenarians and 783 records of controls were obtained. Analysis with multivariate logistic regression found the existence of both general and gender-specific predictors of human longevity. General predictors common for men and women are paternal and maternal longevity. Gender-specific predictors of male longevity are occupation as a farmer at age 40, Northeastern region of birth in the United States, and birth in the second half of year. A gender-specific predictor of female longevity is the availability of radio in the household according to the 1930 U.S. census. Given the importance of familial longevity as an independent predictor of survival to advanced ages, we conducted a comparative study of biological and nonbiological relatives of centenarians using a larger sample of 1,945 validated U.S. centenarians born in 1880–1895. We found that male gender of centenarian has a significant positive effect on survival of adult male relatives (brothers and fathers) but not female blood relatives. Life span of centenarian siblings-in-law is lower compared to life span of centenarian siblings and does not depend on centenarian gender. Wives of male centenarians (who share lifestyle and living conditions) have a significantly better survival

  17. Genome Sequencing Fishes out Longevity Genes.

    PubMed

    Lakhina, Vanisha; Murphy, Coleen T

    2015-12-01

    Understanding the molecular basis underlying aging is critical if we are to fully understand how and why we age-and possibly how to delay the aging process. Up until now, most longevity pathways were discovered in invertebrates because of their short lifespans and availability of genetic tools. Now, Reichwald et al. and Valenzano et al. independently provide a reference genome for the short-lived African turquoise killifish, establishing its role as a vertebrate system for aging research. PMID:26638067

  18. Genetic Signatures of Exceptional Longevity in Humans

    PubMed Central

    Sebastiani, Paola; Solovieff, Nadia; DeWan, Andrew T.; Walsh, Kyle M.; Puca, Annibale; Hartley, Stephen W.; Melista, Efthymia; Andersen, Stacy; Dworkis, Daniel A.; Wilk, Jemma B.; Myers, Richard H.; Steinberg, Martin H.; Montano, Monty; Baldwin, Clinton T.; Hoh, Josephine; Perls, Thomas T.

    2012-01-01

    Like most complex phenotypes, exceptional longevity is thought to reflect a combined influence of environmental (e.g., lifestyle choices, where we live) and genetic factors. To explore the genetic contribution, we undertook a genome-wide association study of exceptional longevity in 801 centenarians (median age at death 104 years) and 914 genetically matched healthy controls. Using these data, we built a genetic model that includes 281 single nucleotide polymorphisms (SNPs) and discriminated between cases and controls of the discovery set with 89% sensitivity and specificity, and with 58% specificity and 60% sensitivity in an independent cohort of 341 controls and 253 genetically matched nonagenarians and centenarians (median age 100 years). Consistent with the hypothesis that the genetic contribution is largest with the oldest ages, the sensitivity of the model increased in the independent cohort with older and older ages (71% to classify subjects with an age at death>102 and 85% to classify subjects with an age at death>105). For further validation, we applied the model to an additional, unmatched 60 centenarians (median age 107 years) resulting in 78% sensitivity, and 2863 unmatched controls with 61% specificity. The 281 SNPs include the SNP rs2075650 in TOMM40/APOE that reached irrefutable genome wide significance (posterior probability of association = 1) and replicated in the independent cohort. Removal of this SNP from the model reduced the accuracy by only 1%. Further in-silico analysis suggests that 90% of centenarians can be grouped into clusters characterized by different “genetic signatures” of varying predictive values for exceptional longevity. The correlation between 3 signatures and 3 different life spans was replicated in the combined replication sets. The different signatures may help dissect this complex phenotype into sub-phenotypes of exceptional longevity. PMID:22279548

  19. A cotton miRNA is involved in regulation of plant response to salt stress

    PubMed Central

    Gao, Shuai; Yang, Lu; Zeng, Hou Qing; Zhou, Zhao Sheng; Yang, Zhi Min; Li, Hua; Sun, Di; Xie, Fuliang; Zhang, Baohong

    2016-01-01

    The present study functionally identified a new microRNA (microRNA ovual line 5, miRNVL5) with its target gene GhCHR from cotton (Gossypium hirsutum). The sequence of miRNVL5 precursor is 104 nt long, with a well developed secondary structure. GhCHR contains two DC1 and three PHD Cys/His-rich domains, suggesting that GhCHR encodes a zinc-finger domain-containing transcription factor. miRNVL5 and GhCHR express at various developmental stages of cotton. Under salt stress (50–400 mM NaCl), miRNVL5 expression was repressed, with concomitant high expression of GhCHR in cotton seedlings. Ectopic expression of GhCHR in Arabidopsis conferred salt stress tolerance by reducing Na+ accumulation in plants and improving primary root growth and biomass. Interestingly, Arabidopsis constitutively expressing miRNVL5 showed hypersensitivity to salt stress. A GhCHR orthorlous gene At2g44380 from Arabidopsis that can be cleaved by miRNVL5 was identified by degradome sequencing, but no confidential miRNVL5 homologs in Arabidopsis have been identified. Microarray analysis of miRNVL5 transgenic Arabidopsis showed six downstream genes (CBF1, CBF2, CBF3, ERF4, AT3G22920, and AT3G49200), which were induced by salt stress in wild-type but repressed in miRNVL5-expressing Arabidopsis. These results indicate that miRNVL5 is involved in regulation of plant response to salt stress. PMID:26813144

  20. Enhancement of stress resilience through Hdac6-mediated regulation of glucocorticoid receptor chaperone dynamics

    PubMed Central

    Jochems, Jeanine; Teegarden, Sarah L; Chen, Yong; Boulden, Janette; Challis, Collin; Ben-Dor, Gabriel A; Kim, Sangwon F; Berton, Olivier

    2014-01-01

    Background Acetylation of Hsp90 regulates downstream hormone signaling via the glucocorticoid receptor (GR), but the role of this molecular mechanism in stress homeostasis remains poorly understood. We tested whether acetylation of Hsp90 in the brain predicts and modulates the behavioral sequelae of a mouse model of social stress. Methods Mice subjected to chronic social defeat stress (CSDS) were stratified into resilient and vulnerable subpopulations. HPA axis function was probed using a DEX/CRF test. Hsp90 acetylation, Hsp90-GR interactions and GR translocation were measured in the dorsal raphe nucleus (DRN). To manipulate Hsp90 acetylation, we pharmacologically inhibited Hdac6, a known deacetylase of Hsp90 or overexpressed a point-mutant that mimics the hyperacetylated state of Hsp90 at lysine K294 Results Lower acetylated Hsp90, higher GR-Hsp90 association and enhanced GR translocation were observed in DRN of vulnerable mice after CSDS. Administration of ACY-738, an Hdac6-selective inhibitor, led to Hsp90 hyperacetylation in brain and in neuronal culture. In cell-based assays, ACY-738 increased the relative association of Hsp90 with FKBP51 versus FKBP52 and inhibited hormone-induced GR translocation. This effect was replicated by overexpressing the acetylation-mimic point-mutant of Hsp90. In vivo, ACY-738 promoted resilience to CSDS and serotonin-selective viral overexpression of the acetylation-mimic mutant of Hsp90 in raphe neurons reproduced the behaviroral effect of ACY-738. Conclusions Hyperacetylation of Hsp90 is a predictor and causal molecular determinant of stress resilience in mice. Brain-penetrant Hdac6 inhibitors increase Hsp90 acetylation and modulate GR chaperone dynamics offering a promising strategy to curtail deleterious socioaffective effects of stress and glucocorticoids. PMID:25442004

  1. Khat use and trait anger: effects on affect regulation during an acute stressful challenge.

    PubMed

    Bongard, Stephan; al'Absi, Mustafa; Khalil, Najat Sayem; Al Habori, Molham

    2011-01-01

    Khat (Catha edulis) is a widely used stimulating drug often consumed in daily routine in Yemen and East African countries. Chewing khat acutely elicits states of euphoria and feelings of well-being which later shift into emotional instability and low mood. Little is known about emotional regulation in habitual khat chewers. In this study, we compared self-reports on trait anger as well as positive and negative affect responses to a mental arithmetic challenge. Participants included 135 men and women from Yemen who chew khat regularly, occasionally or not at all. Participants attended a laboratory session that involved resting periods and performing a math challenge. Analyses of variance and regression show that regular khat chewing is associated with higher trait anger, more pronounced negative responses during stress and less pronounced positive emotional states. These results suggest that regular khat chewing is associated with disturbances in emotion regulation processes. PMID:21860244

  2. Cell stress-regulated human major histocompatibility complex class I gene expressed in gastrointestinal epithelium.

    PubMed Central

    Groh, V; Bahram, S; Bauer, S; Herman, A; Beauchamp, M; Spies, T

    1996-01-01

    Conventional major histocompatibility complex (MHC) class I genes encode molecules that present intracellular peptide antigens to T cells. They are ubiquitously expressed and regulated by interferon gamma. Two highly divergent human MHC class I genes, MICA and MICB, are regulated by promoter heat shock elements similar to those of HSP70 genes. MICA encodes a cell surface glycoprotein, which is not associated with beta 2-microglobulin, is conformationally stable independent of conventional class I peptide ligands, and almost exclusively expressed in gastrointestinal epithelium. Thus, this MHC class I molecule may function as an indicator of cell stress and may be recognized by a subset of gut mucosal T cells in an unusual interaction. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 PMID:8901601

  3. Up-regulation of 2-oxoglutarate dehydrogenase as a stress response.

    PubMed

    Graf, Anastasia; Trofimova, Lidia; Loshinskaja, Alexandra; Mkrtchyan, Garik; Strokina, Anastasiia; Lovat, Maxim; Tylicky, Adam; Strumilo, Slawomir; Bettendorff, Lucien; Bunik, Victoria I

    2013-01-01

    2-Oxoglutarate dehydrogenase multienzyme complex (OGDHC) operates at a metabolic cross-road, mediating Ca(2+)- and ADP-dependent signals in mitochondria. Here, we test our hypothesis that OGDHC plays a major role in the neurotransmitter metabolism and associated stress response. This possibility was assessed using succinyl phosphonate (SP), a highly specific and efficient in vivo inhibitor of OGDHC. Animals exposed to toxicants (SP, ethanol or MnCl(2)), trauma or acute hypoxia showed intrinsic up-regulation of OGDHC in brain and heart. The known mechanism of the SP action as OGDHC inhibitor pointed to the up-regulation triggered by the enzyme impairment. The animal behavior and skeletal muscle or heart performance were tested to correlate physiology with the OGDHC regulation and associated changes in the glutamate and cellular energy status. The SP-treated animals exhibited interdependent changes in the brain OGDHC activity, glutamate level and cardiac autonomic balance, suggesting the neurotransmitter role of glutamate to be involved in the changed heart performance. Energy insufficiency after OGDHC inhibition was detectable neither in animals up to 25 mg/kg SP, nor in cell culture during 24 h incubation with 0.1 mM SP. However, in animals subjected to acute ethanol intoxication SP did evoke energy deficit, decreasing muscular strength and locomotion and increasing the narcotic sleep duration. This correlated with the SP-induced decrease in NAD(P)H levels of the ethanol-exposed neurons. Thus, we show the existence of natural mechanisms to up-regulate mammalian OGDHC in response to stress, with both the glutamate neurotransmission and energy production potentially involved in the OGDHC impact on physiological performance. This article is part of a Directed Issue entitled: Bioenergetic dysfunction, adaptation and therapy. PMID:22814169

  4. NFAT5 in cellular adaptation to hypertonic stress - regulations and functional significance.

    PubMed

    Cheung, Chris Yk; Ko, Ben Cb

    2013-01-01

    The Nuclear Factor of Activated T Cells-5 (NFAT5), also known as OREBP or TonEBP, is a member of the nuclear factors of the activated T cells family of transcription factors. It is also the only known tonicity-regulated transcription factor in mammals. NFAT5 was initially known for its role in the hypertonic kidney inner medulla for orchestrating a genetic program to restore the cellular homeostasis. Emerging evidence, however, suggests that NFAT5 might play a more diverse functional role, including a pivotal role in blood pressure regulation and the development of autoimmune diseases. Despite the growing significance of NFAT5 in physiology and diseases, our understanding of how its activity is regulated remains very limited. Furthermore, how changes in tonicities are converted into functional outputs via NFAT5 remains elusive. Therefore, this review aims to summarize our current knowledge on the functional roles of NFAT5 in osmotic stress adaptation and the signaling pathways that regulate its activity. PMID:23618372

  5. An electrocortical investigation of voluntary emotion regulation in combat-related posttraumatic stress disorder.

    PubMed

    Fitzgerald, Jacklynn M; MacNamara, Annmarie; DiGangi, Julia A; Kennedy, Amy E; Rabinak, Christine A; Patwell, Ryan; Greenstein, Justin E; Proescher, Eric; Rauch, Sheila A M; Hajcak, Greg; Phan, K Luan

    2016-03-30

    Posttraumatic stress disorder (PTSD) - a debilitating disorder characterized by severe deficits in emotion regulation - is prevalent among U.S. military veterans. Research into the pathophysiology of PTSD has focused primarily on emotional reactivity, showing evidence of heightened neural response during negative affect provocation. By comparison, studies of brain functioning during the voluntary regulation of negative affect are limited. In the current study, combat-exposed U.S. military veterans with (n=25) and without (n=25) PTSD performed an emotion regulation task during electroencephalographic (EEG) recording. The late positive potential (LPP) was used as a measure of sustained attention toward, and processing of, negative and neutral pictures, and was scored prior to and after instructions to either maintain or down-regulate emotional response using the strategy of cognitive reappraisal. Results showed that groups did not differ in picture-elicited LPP amplitude either prior to or during cognitive reappraisal; reappraisal reduced the LPP in both groups over time. Time-dependent increases in LPP amplitude as a function of emotional reactivity maintenance were evident in the non-PTSD group only. This latter finding may signal PTSD-related deficits in sustained engagement with emotion-processing over the course of several seconds. PMID:26922156

  6. Differential expression of calcium-regulated SlSRs in response to abiotic and biotic stresses in tomato fruit

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Calcium has been shown to increase stress tolerance, enhance fruit firmness and reduce decay. Previously we reported that seven tomato SlSRs encode calcium/calmodulin-regulated proteins, and that their expressions are developmentally regulated during fruit development and ripening, and are also resp...

  7. Abscisic acid regulates root growth under osmotic stress conditions via an interacting hormonal network with cytokinin, ethylene and auxin.

    PubMed

    Rowe, James H; Topping, Jennifer F; Liu, Junli; Lindsey, Keith

    2016-07-01

    Understanding the mechanisms regulating root development under drought conditions is an important question for plant biology and world agriculture. We examine the effect of osmotic stress on abscisic acid (ABA), cytokinin and ethylene responses and how they mediate auxin transport, distribution and root growth through effects on PIN proteins. We integrate experimental data to construct hormonal crosstalk networks to formulate a systems view of root growth regulation by multiple hormones. Experimental analysis shows: that ABA-dependent and ABA-independent stress responses increase under osmotic stress, but cytokinin responses are only slightly reduced; inhibition of root growth under osmotic stress does not require ethylene signalling, but auxin can rescue root growth and meristem size; osmotic stress modulates auxin transporter levels and localization, reducing root auxin concentrations; PIN1 levels are reduced under stress in an ABA-dependent manner, overriding ethylene effects; and the interplay among ABA, ethylene, cytokinin and auxin is tissue-specific, as evidenced by differential responses of PIN1 and PIN2 to osmotic stress. Combining experimental analysis with network construction reveals that ABA regulates root growth under osmotic stress conditions via an interacting hormonal network with cytokinin, ethylene and auxin. PMID:26889752

  8. Role of Mechanical Stress in Regulating Airway Surface Hydration and Mucus Clearance Rates

    PubMed Central

    Button, Brian; Boucher, Richard C.

    2008-01-01

    Effective clearance of mucus is a critical innate airway defense mechanism, and under appropriate conditions, can be stimulated to enhance clearance of inhaled pathogens. It has become increasingly clear that extracellular nucleotides (ATP and UTP) and nucleosides (adenosine) are important regulators of mucus clearance in the airways as a result of their ability to stimulate fluid secretion, mucus hydration, and cilia beat frequency (CBF). One ubiquitous mechanism to stimulate ATP release is through external mechanical stress. This article addresses the role of physiologically-relevant mechanical forces in the lung and their effects on regulating mucociliary clearance (MCC). The effects of mechanical forces on the stimulating ATP release, fluid secretion, CBF, and MCC are discussed. Also discussed is evidence suggesting that airway hydration and stimulation of MCC by stress-mediated ATP release may play a role in several therapeutic strategies directed at improving mucus clearance in patients with obstructive lung diseases, including cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). PMID:18585484

  9. Enhancer of Rudimentary Homolog Affects the Replication Stress Response through Regulation of RNA Processing

    PubMed Central

    Kavanaugh, Gina; Zhao, Runxiang; Guo, Yan; Mohni, Kareem N.; Glick, Gloria; Lacy, Monica E.; Hutson, M. Shane; Ascano, Manuel

    2015-01-01

    Accurate replication of DNA is imperative for the maintenance of genomic integrity. We identified Enhancer of Rudimentary Homolog (ERH) using a whole-genome RNA interference (RNAi) screen to discover novel proteins that function in the replication stress response. Here we report that ERH is important for DNA replication and recovery from replication stress. ATR pathway activity is diminished in ERH-deficient cells. The reduction in ATR signaling corresponds to a decrease in the expression of multiple ATR pathway genes, including ATR itself. ERH interacts with multiple RNA processing complexes, including splicing regulators. Furthermore, splicing of ATR transcripts is deficient in ERH-depleted cells. Transcriptome-wide analysis indicates that ERH depletion affects the levels of ∼1,500 transcripts, with DNA replication and repair genes being highly enriched among those with reduced expression. Splicing defects were evident in ∼750 protein-coding genes, which again were enriched for DNA metabolism genes. Thus, ERH regulation of RNA processing is needed to ensure faithful DNA replication and repair. PMID:26100022

  10. Transcriptional regulation of ferritin and antioxidant genes by HIPK2 under genotoxic stress.

    PubMed

    Hailemariam, Kiros; Iwasaki, Kenta; Huang, Bo-Wen; Sakamoto, Kensuke; Tsuji, Yoshiaki

    2010-11-15

    ATF1 (activating transcription factor 1), a stimulus-induced CREB family transcription factor, plays important roles in cell survival and proliferation. Phosphorylation of ATF1 at Ser63 by PKA (cAMP-dependent protein kinase) and related kinases was the only known post-translational regulatory mechanism of ATF1. Here, we found that HIPK2 (homeodomain-interacting protein kinase 2), a DNA-damage-responsive nuclear kinase, is a new ATF1 kinase that phosphorylates Ser198 but not Ser63. ATF1 phosphorylation by HIPK2 activated ATF1 transcription function in the GAL4-reporter system. ATF1 is a transcriptional repressor of ferritin H, the major intracellular iron storage gene, through an ARE (antioxidant-responsive element). HIPK2 overrode the ATF1-mediated ARE repression in a kinase-activity-dependent manner in HepG2 cells. Furthermore, DNA-damage-inducing agents doxorubicin, etoposide and sodium arsenite induced ferritin H mRNA expression in HIPK2(+/+) MEF cells, whereas it was significantly impaired in HIPK2(-/-) MEF cells. Induction of other ARE-regulated detoxification genes such as NQO1 (NADPH quinone oxidoreductase 1), GST (glutathione S-transferase) and HO1 (heme oxygenase 1) by genotoxic stress was also decreased in HIPK2-deficient cells. Taken together, these results suggest that HIPK2 is a new ATF1 kinase involved in the regulation of ferritin H and other antioxidant detoxification genes in genotoxic stress conditions. PMID:20980392

  11. Regulation of shear stress on rolling behaviors of HL-60 cells on P-selectin

    NASA Astrophysics Data System (ADS)

    Ling, YingChen; Fang, Ying; Yang, XiaoFang; Li, QuHuan; Lin, QinYong; Wu, JianHua

    2014-10-01

    Circulating leukocytes in trafficking to the inflammatory sites, will be first tether to, and then roll on the vascular surface. This event is mediated through specific interaction of P-selectin and P-selectin glycoprotein ligand-1 (PSGL-1), and regulated by hemodynamics. Poor data were reported in understanding P-selectin-mediated rolling. With the flow chamber technique, we herein observed HL-60 cell rolling on P-selectin with or without 3% Ficoll at various wall shear stresses from 0.05 to 0.4 dyn/cm2. The results demonstrated that force rather than transport regulated the rolling, similar to rolling on L- and E-selectin. The rolling was accelerated quickly by an increasing force below the optimal shear threshold of 0.15 dyn/cm2 first and then followed by a slowly decelerating phase starting at the optimum, showing a catch-slip transition and serving as a mechanism for the rolling. The catch-slip transition was completely reflected to the tether lifetime and other rolling parameters, such as the mean and fractional stop time. The narrow catch bond regime stabilized the rolling quickly, through steeply increasing fractional stop time to a plateau of about 0.85. Data presented here suggest that the low shear stress threshold serves as a mechanism for most cell rolling events through P-selectin.

  12. Stress from Nucleotide Depletion Activates the Transcriptional Regulator HEXIM1 to Suppress Melanoma.

    PubMed

    Tan, Justin L; Fogley, Rachel D; Flynn, Ryan A; Ablain, Julien; Yang, Song; Saint-André, Violaine; Fan, Zi Peng; Do, Brian T; Laga, Alvaro C; Fujinaga, Koh; Santoriello, Cristina; Greer, Celeste B; Kim, Yoon Jung; Clohessy, John G; Bothmer, Anne; Pandell, Nicole; Avagyan, Serine; Brogie, John E; van Rooijen, Ellen; Hagedorn, Elliott J; Shyh-Chang, Ng; White, Richard M; Price, David H; Pandolfi, Pier Paolo; Peterlin, B Matija; Zhou, Yi; Kim, Tae Hoon; Asara, John M; Chang, Howard Y; Young, Richard A; Zon, Leonard I

    2016-04-01

    Studying cancer metabolism gives insight into tumorigenic survival mechanisms and susceptibilities. In melanoma, we identify HEXIM1, a transcription elongation regulator, as a melanoma tumor suppressor that responds to nucleotide stress. HEXIM1 expression is low in melanoma. Its overexpression in a zebrafish melanoma model suppresses cancer formation, while its inactivation accelerates tumor onset in vivo. Knockdown of HEXIM1 rescues zebrafish neural crest defects and human melanoma proliferation defects that arise from nucleotide depletion. Under nucleotide stress, HEXIM1 is induced to form an inhibitory complex with P-TEFb, the kinase that initiates transcription elongation, to inhibit elongation at tumorigenic genes. The resulting alteration in gene expression also causes anti-tumorigenic RNAs to bind to and be stabilized by HEXIM1. HEXIM1 plays an important role in inhibiting cancer cell-specific gene transcription while also facilitating anti-cancer gene expression. Our study reveals an important role f